Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is associated with poor prognosis. Despite years of research and improvements in chemotherapy regimens, the 5-year survival rate of PDAC remains dismal. Therapies for PDAC often face resistance owing in large part to an extensive desmoplastic stromal matrix. Modelling PDAC ex vivo to investigate novel therapeutics is challenging due to the complex tumour microenvironment and its heterogeneity in native tumours. Development of novel therapies is needed to improve PDAC survival rates, for which disease models that recapitulate the tumour biology are expected to bear utility. This review focuses on the existing preclinical models for human PDAC and discusses advancements in tissue remodelling to guide translational PDAC research. Further emphasis is placed on photodynamic therapy (PDT) due to the ability of this treatment modality to not only directly kill cancer cells by minimally invasive means, but also to perturb the tumour microenvironment and elicit a post-therapeutic anti-tumour immune response. Accordingly, more complex preclinical models that feature multiple biologically relevant PDAC components are needed to develop translatable PDT regimens in a preclinical setting.

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences 142 00 Prague Czech Republic

Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences Utrecht University 3584 CG Utrecht The Netherlands

Engineered Therapeutics Group Department of Advanced Organ Bioengineering and Therapeutics Technical Medical Centre University of Twente 7522 NB Enschede The Netherlands

Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics Department of Pharmaceutics College of Medicine Jiaxing University Jiaxing 314001 China

Leeds Institute of Medical Research St James's University Teaching Hospital Leeds LS9 7TF UK

Membrane Biochemistry and Biophysics Department of Chemistry Faculty of Science Utrecht University 3584 CS Utrecht The Netherlands

School of Medicine The University of Leeds LS2 9JT Leeds UK

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Peng J., Sun B.F., Chen C.Y., Zhou J.Y., Chen Y.S., Chen H., Liu L., Huang D., Jiang J., Cui G.S., et al. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res. 2019;29:725–738. doi: 10.1038/s41422-019-0195-y. PubMed DOI PMC

Buscail L., Bournet B., Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat. Rev. Gastroenterol. Hepatol. 2020;17:153–168. doi: 10.1038/s41575-019-0245-4. PubMed DOI

Conroy T., Hammel P., Hebbar M., Ben Abdelghani M., Wei A.C., Raoul J.L., Chone L., Francois E., Artru P., Biagi J.J., et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N. Engl. J. Med. 2018;379:2395–2406. doi: 10.1056/NEJMoa1809775. PubMed DOI

Strobel O., Neoptolemos J., Jager D., Buchler M.W. Optimizing the outcomes of pancreatic cancer surgery. Nat. Rev. Clin. Oncol. 2019;16:11–26. doi: 10.1038/s41571-018-0112-1. PubMed DOI

Oettle H., Neuhaus P., Hochhaus A., Hartmann J.T., Gellert K., Ridwelski K., Niedergethmann M., Zulke C., Fahlke J., Arning M.B., et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: The CONKO-001 randomized trial. JAMA. 2013;310:1473–1481. doi: 10.1001/jama.2013.279201. PubMed DOI

Strobel O., Hank T., Hinz U., Bergmann F., Schneider L., Springfeld C., Jager D., Schirmacher P., Hackert T., Buchler M.W. Pancreatic Cancer Surgery: The New R-status Counts. Ann. Surg. 2017;265:565–573. doi: 10.1097/SLA.0000000000001731. PubMed DOI

Hank T., Hinz U., Tarantino I., Kaiser J., Niesen W., Bergmann F., Hackert T., Buchler M.W., Strobel O. Validation of at least 1 mm as cut-off for resection margins for pancreatic adenocarcinoma of the body and tail. Br. J. Surg. 2018;105:1171–1181. doi: 10.1002/bjs.10842. PubMed DOI

Vitali F., Pfeifer L., Janson C., Goertz R.S., Neurath M.F., Strobel D., Wildner D. Quantitative perfusion analysis in pancreatic contrast enhanced ultrasound (DCE-US): A promising tool for the differentiation between autoimmune pancreatitis and pancreatic cancer. Z. Gastroenterol. 2015;53:1175–1181. doi: 10.1055/s-0041-103847. PubMed DOI

Liu X., Fu Y., Chen Q., Wu J., Gao W., Jiang K., Miao Y., Wei J. Predictors of distant metastasis on exploration in patients with potentially resectable pancreatic cancer. BMC Gastroenterol. 2018;18:168. doi: 10.1186/s12876-018-0891-y. PubMed DOI PMC

Versteijne E., Suker M., Groothuis K., Akkermans-Vogelaar J.M., Besselink M.G., Bonsing B.A., Buijsen J., Busch O.R., Creemers G.M., van Dam R.M., et al. Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial. J. Clin. Oncol. 2020;38:1763–1773. doi: 10.1200/JCO.19.02274. PubMed DOI PMC

Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492. PubMed DOI

Dangi-Garimella S., Sahai V., Ebine K., Kumar K., Munshi H.G. Three-dimensional collagen I promotes gemcitabine resistance in vitro in pancreatic cancer cells through HMGA2-dependent histone acetyltransferase expression. PLoS ONE. 2013;8:e64566. doi: 10.1371/journal.pone.0064566. PubMed DOI PMC

Zhao J., Wang H., Hsiao C.H., Chow D.S., Koay E.J., Kang Y., Wen X., Huang Q., Ma Y., Bankson J.A., et al. Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy. Biomaterials. 2018;159:215–228. doi: 10.1016/j.biomaterials.2018.01.014. PubMed DOI PMC

Sensi F., D’Angelo E., Biccari A., Marangio A., Battisti G., Crotti S., Fassan M., Laterza C., Giomo M., Elvassore N., et al. Establishment of a human 3D pancreatic adenocarcinoma model based on a patient-derived extracellular matrix scaffold. Transl. Res. 2023;253:57–67. doi: 10.1016/j.trsl.2022.08.015. PubMed DOI

Mu P., Zhou S., Lv T., Xia F., Shen L., Wan J., Wang Y., Zhang H., Cai S., Peng J., et al. Newly developed 3D in vitro models to study tumor-immune interaction. J. Exp. Clin. Cancer Res. 2023;42:81. doi: 10.1186/s13046-023-02653-w. PubMed DOI PMC

Karimnia V., Stanley M.E., Fitzgerald C.T., Rizvi I., Slack F.J., Celli J.P. Photodynamic Stromal Depletion Enhances Therapeutic Nanoparticle Delivery in 3D Pancreatic Ductal Adenocarcinoma Tumor Models. Photochem. Photobiol. 2023;99:120–131. doi: 10.1111/php.13663. PubMed DOI PMC

Lintern N., Smith A.M., Jayne D.G., Khaled Y.S. Photodynamic Stromal Depletion in Pancreatic Ductal Adenocarcinoma. Cancers. 2023;15:4135. doi: 10.3390/cancers15164135. PubMed DOI PMC

Mei L., Du W., Ma W.W. Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: Controversies and promises. J. Gastrointest. Oncol. 2016;7:487–494. doi: 10.21037/jgo.2016.03.03. PubMed DOI PMC

Schnittert J., Bansal R., Mardhian D.F., van Baarlen J., Ostman A., Prakash J. Integrin alpha11 in pancreatic stellate cells regulates tumor stroma interaction in pancreatic cancer. FASEB J. 2019;33:6609–6621. doi: 10.1096/fj.201802336R. PubMed DOI

Schnittert J., Bansal R., Prakash J. Targeting Pancreatic Stellate Cells in Cancer. Trends Cancer. 2019;5:128–142. doi: 10.1016/j.trecan.2019.01.001. PubMed DOI

Du W., Pasca di Magliano M., Zhang Y. Therapeutic Potential of Targeting Stromal Crosstalk-Mediated Immune Suppression in Pancreatic Cancer. Front. Oncol. 2021;11:682217. doi: 10.3389/fonc.2021.682217. PubMed DOI PMC

Bauer C., Kühnemuth B., Duewell P., Ormanns S., Gress T., Schnurr M. Prevailing over T cell exhaustion: New developments in the immunotherapy of pancreatic cancer. Cancer Lett. 2016;381:259–268. doi: 10.1016/j.canlet.2016.02.057. PubMed DOI

Raskov H., Orhan A., Christensen J.P., Gögenur I. Cytotoxic CD8. Br. J. Cancer. 2021;124:359–367. doi: 10.1038/s41416-020-01048-4. PubMed DOI PMC

Tormoen G.W., Crittenden M.R., Gough M.J. Role of the immunosuppressive microenvironment in immunotherapy. Adv. Radiat. Oncol. 2018;3:520–526. doi: 10.1016/j.adro.2018.08.018. PubMed DOI PMC

Longo V., Brunetti O., Gnoni A., Cascinu S., Gasparini G., Lorusso V., Ribatti D., Silvestris N. Angiogenesis in pancreatic ductal adenocarcinoma: A controversial issue. Oncotarget. 2016;7:58649–58658. doi: 10.18632/oncotarget.10765. PubMed DOI PMC

Le Large T.Y., Mantini G., Meijer L.L., Pham T.V., Funel N., van Grieken N.C., Kok B., Knol J., van Laarhoven H.W., Piersma S.R., et al. Microdissected pancreatic cancer proteomes reveal tumor heterogeneity and therapeutic targets. JCI Insight. 2020;5:e138290. doi: 10.1172/jci.insight.138290. PubMed DOI PMC

Pan Z., Li L., Fang Q., Zhang Y., Hu X., Qian Y., Huang P. Analysis of dynamic molecular networks for pancreatic ductal adenocarcinoma progression. Cancer Cell Int. 2018;18:214. doi: 10.1186/s12935-018-0718-5. PubMed DOI PMC

Shen Y., Pu K., Zheng K., Ma X., Qin J., Jiang L., Li J. Differentially Expressed microRNAs in MIA PaCa-2 and PANC-1 Pancreas Ductal Adenocarcinoma Cell Lines are Involved in Cancer Stem Cell Regulation. Int. J. Mol. Sci. 2019;20:4473. doi: 10.3390/ijms20184473. PubMed DOI PMC

Khosravani F., Mir H., Mirzaei A., Kobarfard F., Bardania H., Hosseini E. Arsenic trioxide and Erlotinib loaded in RGD-modified nanoliposomes for targeted combination delivery to PC3 and PANC-1 cell lines. Biotechnol. Appl. Biochem. 2023;70:811–823. doi: 10.1002/bab.2401. PubMed DOI

Malinda R.R., Zeeberg K., Sharku P.C., Ludwig M.Q., Pedersen L.B., Christensen S.T., Pedersen S.F. TGFβ Signaling Increases Net Acid Extrusion, Proliferation and Invasion in Panc-1 Pancreatic Cancer Cells: SMAD4 Dependence and Link to Merlin/NF2 Signaling. Front. Oncol. 2020;10:687. doi: 10.3389/fonc.2020.00687. PubMed DOI PMC

Schnittert J., Heinrich M.A., Kuninty P.R., Storm G., Prakash J. Reprogramming tumor stroma using an endogenous lipid lipoxin A4 to treat pancreatic cancer. Cancer Lett. 2018;420:247–258. doi: 10.1016/j.canlet.2018.01.072. PubMed DOI

Kuninty P.R., Bojmar L., Tjomsland V., Larsson M., Storm G., Ostman A., Sandstrom P., Prakash J. MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor. Oncotarget. 2016;7:16396–16408. doi: 10.18632/oncotarget.7651. PubMed DOI PMC

Gunti S., Hoke A.T.K., Vu K.P., London N.R. Organoid and Spheroid Tumor Models: Techniques and Applications. Cancers. 2021;13:874. doi: 10.3390/cancers13040874. PubMed DOI PMC

Ding Y., Mei W., Zheng Z., Cao F., Liang K., Jia Y., Wang Y., Liu D., Li J., Li F. Exosomes secreted from human umbilical cord mesenchymal stem cells promote pancreatic ductal adenocarcinoma growth by transferring miR-100-5p. Tissue Cell. 2021;73:101623. doi: 10.1016/j.tice.2021.101623. PubMed DOI

Suri R., Zimmerman J.W., Burkhart R.A. Modeling human pancreatic ductal adenocarcinoma for translational research: Current options, challenges, and prospective directions. Ann. Pancreat. Cancer. 2020;3:17. doi: 10.21037/apc-20-29. PubMed DOI PMC

Hwang C.I., Boj S.F., Clevers H., Tuveson D.A. Preclinical models of pancreatic ductal adenocarcinoma. J. Pathol. 2016;238:197–204. doi: 10.1002/path.4651. PubMed DOI PMC

Audero M.M., Carvalho T.M.A., Ruffinatti F.A., Loeck T., Yassine M., Chinigo G., Folcher A., Farfariello V., Amadori S., Vaghi C., et al. Acidic Growth Conditions Promote Epithelial-to-Mesenchymal Transition to Select More Aggressive PDAC Cell Phenotypes In Vitro. Cancers. 2023;15:2572. doi: 10.3390/cancers15092572. PubMed DOI PMC

Rodrigues J., Heinrich M.A., Teixeira L.M., Prakash J. 3D In Vitro Model (R)evolution: Unveiling Tumor-Stroma Interactions. Trends Cancer. 2021;7:249–264. doi: 10.1016/j.trecan.2020.10.009. PubMed DOI

Prakash J., Shaked Y. The Interplay between Extracellular Matrix Remodeling and Cancer Therapeutics. Cancer Discov. 2024;14:1375–1388. doi: 10.1158/2159-8290.CD-24-0002. PubMed DOI PMC

Longati P., Jia X., Eimer J., Wagman A., Witt M.R., Rehnmark S., Verbeke C., Toftgård R., Löhr M., Heuchel R.L. 3D pancreatic carcinoma spheroids induce a matrix-rich, chemoresistant phenotype offering a better model for drug testing. BMC Cancer. 2013;13:95. doi: 10.1186/1471-2407-13-95. PubMed DOI PMC

Rescigno F., Ceriotti L., Meloni M. Extra Cellular Matrix Deposition and Assembly in Dermis Spheroids. Clin. Cosmet. Investig. Dermatol. 2021;14:935–943. doi: 10.2147/CCID.S316707. PubMed DOI PMC

Ncube K.N., Jurgens T., Steenkamp V., Cromarty A.D., van den Bout I., Cordier W. Comparative Evaluation of the Cytotoxicity of Doxorubicin in BT-20 Triple-Negative Breast Carcinoma Monolayer and Spheroid Cultures. Biomedicines. 2023;11:1484. doi: 10.3390/biomedicines11051484. PubMed DOI PMC

Nkune N.W., Simelane N.W.N., Montaseri H., Abrahamse H. Photodynamic Therapy-Mediated Immune Responses in Three-Dimensional Tumor Models. Int. J. Mol. Sci. 2021;22:12618. doi: 10.3390/ijms222312618. PubMed DOI PMC

Roy M., Alix C., Bouakaz A., Serriere S., Escoffre J.M. Tumor Spheroids as Model to Design Acoustically Mediated Drug Therapies: A Review. Pharmaceutics. 2023;15:806. doi: 10.3390/pharmaceutics15030806. PubMed DOI PMC

Gilazieva Z., Ponomarev A., Rutland C., Rizvanov A., Solovyeva V. Promising Applications of Tumor Spheroids and Organoids for Personalized Medicine. Cancers. 2020;12:2727. doi: 10.3390/cancers12102727. PubMed DOI PMC

Kuntze A., Goetsch O., Fels B., Najder K., Unger A., Wilhelmi M., Sargin S., Schimmelpfennig S., Neumann I., Schwab A., et al. Protonation of Piezo1 Impairs Cell-Matrix Interactions of Pancreatic Stellate Cells. Front. Physiol. 2020;11:89. doi: 10.3389/fphys.2020.00089. PubMed DOI PMC

Ware M.J., Keshishian V., Law J.J., Ho J.C., Favela C.A., Rees P., Smith B., Mohammad S., Hwang R.F., Rajapakshe K., et al. Generation of an in vitro 3D PDAC stroma rich spheroid model. Biomaterials. 2016;108:129–142. doi: 10.1016/j.biomaterials.2016.08.041. PubMed DOI PMC

Lee K.-H., Kim T.-H. Recent Advances in Multicellular Tumor Spheroid Generation for Drug Screening. Biosensors. 2021;11:445. doi: 10.3390/bios11110445. PubMed DOI PMC

Dufau I., Frongia C., Sicard F., Dedieu L., Cordelier P., Ausseil F., Ducommun B., Valette A. Multicellular tumor spheroid model to evaluate spatio-temporal dynamics effect of chemotherapeutics: Application to the gemcitabine/CHK1 inhibitor combination in pancreatic cancer. BMC Cancer. 2012;12:15. doi: 10.1186/1471-2407-12-15. PubMed DOI PMC

Maietta I., Martínez-Pérez A., Álvarez R., De Lera Á.R., González-Fernández Á., Simón-Vázquez R. Synergistic Antitumoral Effect of Epigenetic Inhibitors and Gemcitabine in Pancreatic Cancer Cells. Pharmaceuticals. 2022;15:824. doi: 10.3390/ph15070824. PubMed DOI PMC

Wang Z., He R., Dong S., Zhou W. Pancreatic stellate cells in pancreatic cancer: As potential targets for future therapy. Front. Oncol. 2023;13:1185093. doi: 10.3389/fonc.2023.1185093. PubMed DOI PMC

Ferreira L.P., Gaspar V.M., Mendes L., Duarte I.F., Mano J.F. Organotypic 3D decellularized matrix tumor spheroids for high-throughput drug screening. Biomaterials. 2021;275:120983. doi: 10.1016/j.biomaterials.2021.120983. PubMed DOI

Scalise M., Marino F., Salerno L., Cianflone E., Molinaro C., Salerno N., De Angelis A., Viglietto G., Urbanek K., Torella D. From Spheroids to Organoids: The Next Generation of Model Systems of Human Cardiac Regeneration in a Dish. Int. J. Mol. Sci. 2021;22:13180. doi: 10.3390/ijms222413180. PubMed DOI PMC

Khursheed M., Bashyam M.D. Apico-basal polarity complex and cancer. J. Biosci. 2014;39:145–155. doi: 10.1007/s12038-013-9410-z. PubMed DOI

Tsai S., McOlash L., Palen K., Johnson B., Duris C., Yang Q., Dwinell M.B., Hunt B., Evans D.B., Gershan J., et al. Development of primary human pancreatic cancer organoids, matched stromal and immune cells and 3D tumor microenvironment models. BMC Cancer. 2018;18:335. doi: 10.1186/s12885-018-4238-4. PubMed DOI PMC

Neesse A., Michl P., Frese K.K., Feig C., Cook N., Jacobetz M.A., Lolkema M.P., Buchholz M., Olive K.P., Gress T.M., et al. Stromal biology and therapy in pancreatic cancer. Gut. 2011;60:861–868. doi: 10.1136/gut.2010.226092. PubMed DOI

Shinkawa T., Ohuchida K., Nakamura M. Heterogeneity of Cancer-Associated Fibroblasts and the Tumor Immune Microenvironment in Pancreatic Cancer. Cancers. 2022;14:3994. doi: 10.3390/cancers14163994. PubMed DOI PMC

Luo Y., Li Z., Kong Y., He W., Zheng H., An M., Lin Y., Zhang D., Yang J., Zhao Y., et al. KRAS mutant-driven SUMOylation controls extracellular vesicle transmission to trigger lymphangiogenesis in pancreatic cancer. J. Clin. Investig. 2022;132:e157644. doi: 10.1172/JCI157644. PubMed DOI PMC

McGuigan A.J., Coleman H.G., McCain R.S., Kelly P.J., Johnston D.I., Taylor M.A., Turkington R.C. Immune cell infiltrates as prognostic biomarkers in pancreatic ductal adenocarcinoma: A systematic review and meta-analysis. J. Pathol. Clin. Res. 2021;7:99–112. doi: 10.1002/cjp2.192. PubMed DOI PMC

Liu X., Iovanna J., Santofimia-Castaño P. Stroma-targeting strategies in pancreatic cancer: A double-edged sword. J. Physiol. Biochem. 2023;79:213–222. doi: 10.1007/s13105-022-00941-1. PubMed DOI

Stouten I., van Montfoort N., Hawinkels L.J.A.C. The Tango between Cancer-Associated Fibroblasts (CAFs) and Immune Cells in Affecting Immunotherapy Efficacy in Pancreatic Cancer. Int. J. Mol. Sci. 2023;24:8707. doi: 10.3390/ijms24108707. PubMed DOI PMC

Maneshi P., Mason J., Dongre M., Oehlund D. Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits. Front. Cell Dev. Biol. 2021;9:787485. doi: 10.3389/fcell.2021.787485. PubMed DOI PMC

Miyazaki Y., Oda T., Inagaki Y., Kushige H., Saito Y., Mori N., Takayama Y., Kumagai Y., Mitsuyama T., Kida Y.S. Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model. Sci. Rep. 2021;11:4690. doi: 10.1038/s41598-021-84058-3. PubMed DOI PMC

Hwang H.J., Oh M.S., Lee D.W., Kuh H.J. Multiplex quantitative analysis of stroma-mediated cancer cell invasion, matrix remodeling, and drug response in a 3D co-culture model of pancreatic tumor spheroids and stellate cells. J. Exp. Clin. Cancer Res. 2019;38:258. doi: 10.1186/s13046-019-1225-9. PubMed DOI PMC

Knight E., Przyborski S. Advances in 3D cell culture technologies enabling tissue-like structures to be created in vitro. J. Anat. 2015;227:746–756. doi: 10.1111/joa.12257. PubMed DOI PMC

Lee J.H., Kim S.K., Khawar I.A., Jeong S.Y., Chung S., Kuh H.J. Microfluidic co-culture of pancreatic tumor spheroids with stellate cells as a novel 3D model for investigation of stroma-mediated cell motility and drug resistance. J. Exp. Clin. Cancer Res. 2018;37:4. doi: 10.1186/s13046-017-0654-6. PubMed DOI PMC

Jang S.D., Song J., Kim H.A., Im C.N., Khawar I.A., Park J.K., Kuh H.J. Anti-Cancer Activity Profiling of Chemotherapeutic Agents in 3D Co-Cultures of Pancreatic Tumor Spheroids with Cancer-Associated Fibroblasts and Macrophages. Cancers. 2021;13:5955. doi: 10.3390/cancers13235955. PubMed DOI PMC

Kpeglo D., Hughes M.D.G., Dougan L., Haddrick M., Knowles M.A., Evans S.D., Peyman S.A. Modeling the mechanical stiffness of pancreatic ductal adenocarcinoma. Matrix Biol. Plus. 2022;14:100109. doi: 10.1016/j.mbplus.2022.100109. PubMed DOI PMC

Ding L., Zhang Z., Shang D., Cheng J., Yuan H., Wu Y., Song X., Jiang H. α-Smooth muscle actin-positive myofibroblasts, in association with epithelial-mesenchymal transition and lymphogenesis, is a critical prognostic parameter in patients with oral tongue squamous cell carcinoma. J. Oral Pathol. Med. 2014;43:335–343. doi: 10.1111/jop.12143. PubMed DOI

Kaszak I., Witkowska-Piłaszewicz O., Niewiadomska Z., Dworecka-Kaszak B., Ngosa Toka F., Jurka P. Role of Cadherins in Cancer-A Review. Int. J. Mol. Sci. 2020;21:7624. doi: 10.3390/ijms21207624. PubMed DOI PMC

Kim S., You D., Jeong Y., Yu J., Kim S.W., Nam S.J., Lee J.E. TP53 upregulates α-smooth muscle actin expression in tamoxifen-resistant breast cancer cells. Oncol. Rep. 2019;41:1075–1082. doi: 10.3892/or.2018.6910. PubMed DOI

Öhlund D., Handly-Santana A., Biffi G., Elyada E., Almeida A.S., Ponz-Sarvise M., Corbo V., Oni T.E., Hearn S.A., Lee E.J., et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 2017;214:579–596. doi: 10.1084/jem.20162024. PubMed DOI PMC

Priwitaningrum D.L., Blonde J.G., Sridhar A., van Baarlen J., Hennink W.E., Storm G., Le Gac S., Prakash J. Tumor stroma-containing 3D spheroid arrays: A tool to study nanoparticle penetration. J. Control. Release. 2016;244:257–268. doi: 10.1016/j.jconrel.2016.09.004. PubMed DOI

Kuninty P.R., Bansal R., De Geus S.W.L., Mardhian D.F., Schnittert J., van Baarlen J., Storm G., Bijlsma M.F., van Laarhoven H.W., Metselaar J.M., et al. ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer. Sci. Adv. 2019;5:eaax2770. doi: 10.1126/sciadv.aax2770. PubMed DOI PMC

Anane-Adjei A.B., Fletcher N.L., Cavanagh R.J., Houston Z.H., Crawford T., Pearce A.K., Taresco V., Ritchie A.A., Clarke P., Grabowska A.M., et al. Synthesis, characterisation and evaluation of hyperbranched N-(2-hydroxypropyl) methacrylamides for transport and delivery in pancreatic cell lines in vitro and in vivo. Biomater. Sci. 2022;10:2328–2344. doi: 10.1039/D1BM01548F. PubMed DOI

Saito K., Sakaguchi M., Maruyama S., Iioka H., Putranto E.W., Sumardika I.W., Tomonobu N., Kawasaki T., Homma K., Kondo E. Stromal mesenchymal stem cells facilitate pancreatic cancer progression by regulating specific secretory molecules through mutual cellular interaction. J. Cancer. 2018;9:2916–2929. doi: 10.7150/jca.24415. PubMed DOI PMC

Ullah I., Subbarao R.B., Rho G.J. Human mesenchymal stem cells—Current trends and future prospective. Biosci. Rep. 2015;35:e00191. doi: 10.1042/BSR20150025. PubMed DOI PMC

Pednekar K.P., Heinrich M.A., van Baarlen J., Prakash J. Novel 3D microtissues Mimicking the Fibrotic Stroma in Pancreatic Cancer to Study Cellular Interactions and Stroma-Modulating Therapeutics. Cancers. 2021;13:5006. doi: 10.3390/cancers13195006. PubMed DOI PMC

Ammar N., Hildebrandt M., Geismann C., Roder C., Gemoll T., Sebens S., Trauzold A., Schafer H. Monocarboxylate Transporter-1 (MCT1)-Mediated Lactate Uptake Protects Pancreatic Adenocarcinoma Cells from Oxidative Stress during Glutamine Scarcity Thereby Promoting Resistance against Inhibitors of Glutamine Metabolism. Antioxidants. 2023;12:1818. doi: 10.3390/antiox12101818. PubMed DOI PMC

Kitamura F., Semba T., Yasuda-Yoshihara N., Yamada K., Nishimura A., Yamasaki J., Nagano O., Yasuda T., Yonemura A., Tong Y., et al. Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer. JCI Insight. 2023;8:e163022. doi: 10.1172/jci.insight.163022. PubMed DOI PMC

Xu R., Yang J., Ren B., Wang H., Yang G., Chen Y., You L., Zhao Y. Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies. Front. Oncol. 2020;10:572722. doi: 10.3389/fonc.2020.572722. PubMed DOI PMC

Jin M.-Z., Han R.-R., Qiu G.-Z., Ju X.-C., Lou G., Jin W.-L. Organoids: An intermediate modeling platform in precision oncology. Cancer Lett. 2018;414:174–180. doi: 10.1016/j.canlet.2017.11.021. PubMed DOI

Ye L., Swingen C., Zhang J. Induced pluripotent stem cells and their potential for basic and clinical sciences. Curr. Cardiol. Rev. 2013;9:63–72. doi: 10.2174/157340313805076278. PubMed DOI PMC

Zhang Y., Houchen C.W., Li M. Patient-Derived Organoid Pharmacotyping Guides Precision Medicine for Pancreatic Cancer. Clin. Cancer Res. 2022;28:3176–3178. doi: 10.1158/1078-0432.CCR-22-1083. PubMed DOI PMC

Yang H., Wang Y., Wang P., Zhang N., Wang P. Tumor organoids for cancer research and personalized medicine. Cancer Biol. Med. 2021;18:319–332. doi: 10.20892/j.issn.2095-3941.2021.0335. PubMed DOI PMC

Broguiere N., Isenmann L., Hirt C., Ringel T., Placzek S., Cavalli E., Ringnalda F., Villiger L., Züllig R., Lehmann R., et al. Growth of Epithelial Organoids in a Defined Hydrogel. Adv. Mater. 2018;30:e1801621. doi: 10.1002/adma.201801621. PubMed DOI

Schuster B., Junkin M., Kashaf S.S., Romero-Calvo I., Kirby K., Matthews J., Weber C.R., Rzhetsky A., White K.P., Tay S. Automated microfluidic platform for dynamic and combinatorial drug screening of tumor organoids. Nat. Commun. 2020;11:5271. doi: 10.1038/s41467-020-19058-4. PubMed DOI PMC

Aberle M.R., Burkhart R.A., Tiriac H., Damink S.W.M.O., Dejong C.H.C., Tuveson D.A., van Dam R.M. Patient-derived organoid models help define personalized management of gastrointestinal cancer. Br. J. Surg. 2018;105:E48–E60. doi: 10.1002/bjs.10726. PubMed DOI PMC

Boucherit N., Gorvel L., Olive D. 3D Tumor Models and Their Use for the Testing of Immunotherapies. Front. Immunol. 2020;11:603640. doi: 10.3389/fimmu.2020.603640. PubMed DOI PMC

Romero-Calvo I., Weber C.R., Ray M., Brown M., Kirby K., Nandi R.K., Long T.M., Sparrow S.M., Ugolkov A., Qiang W., et al. Human Organoids Share Structural and Genetic Features with Primary Pancreatic Adenocarcinoma Tumors. Mol. Cancer Res. 2019;17:70–83. doi: 10.1158/1541-7786.MCR-18-0531. PubMed DOI PMC

Driehuis E., van Hoeck A., Moore K., Kolders S., Francies H.E., Gulersonmez M.C., Stigter E.C.A., Burgering B., Geurts V., Gracanin A., et al. Pancreatic cancer organoids recapitulate disease and allow personalized drug screening. Proc. Natl. Acad. Sci. USA. 2019;116:26580–26590. doi: 10.1073/pnas.1911273116. PubMed DOI PMC

Zeöld A., Sándor G.O., Kiss A., Soós A.Á., Tölgyes T., Bursics A., Szűcs Á., Harsányi L., Kittel Á., Gézsi A., et al. Shared extracellular vesicle miRNA profiles of matched ductal pancreatic adenocarcinoma organoids and blood plasma samples show the power of organoid technology. Cell. Mol. Life Sci. 2021;78:3005–3020. doi: 10.1007/s00018-020-03703-8. PubMed DOI PMC

Sereti E., Papapostolou I., Dimas K. Pancreatic Cancer Organoids: An Emerging Platform for Precision Medicine? Biomedicines. 2023;11:890. doi: 10.3390/biomedicines11030890. PubMed DOI PMC

Holokai L., Chakrabarti J., Lundy J., Croagh D., Adhikary P., Richards S.S., Woodson C., Steele N., Kuester R., Scott A., et al. Murine- and Human-Derived Autologous Organoid/Immune Cell Co-Cultures as Pre-Clinical Models of Pancreatic Ductal Adenocarcinoma. Cancers. 2020;12:3816. doi: 10.3390/cancers12123816. PubMed DOI PMC

Hennig A., Baenke F., Klimova A., Drukewitz S., Jahnke B., Brückmann S., Secci R., Winter C., Schmäche T., Seidlitz T., et al. Detecting drug resistance in pancreatic cancer organoids guides optimized chemotherapy treatment. J. Pathol. 2022;257:607–619. doi: 10.1002/path.5906. PubMed DOI

Krieger T.G., Le Blanc S., Jabs J., Ten F.W., Ishaque N., Jechow K., Debnath O., Leonhardt C.-S., Giri A., Eils R., et al. Single-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy. Nat. Commun. 2021;12:5826. doi: 10.1038/s41467-021-26059-4. PubMed DOI PMC

Lee S., Shanti A. Effect of Exogenous pH on Cell Growth of Breast Cancer Cells. Int. J. Mol. Sci. 2021;22:9910. doi: 10.3390/ijms22189910. PubMed DOI PMC

Baker L.A., Tiriac H., Clevers H., Tuveson D.A. Modeling pancreatic cancer with organoids. Trends Cancer. 2016;2:176–190. doi: 10.1016/j.trecan.2016.03.004. PubMed DOI PMC

Givant-Horwitz V., Davidson B., Reich R. Laminin-induced signaling in tumor cells: The role of the M(r) 67,000 laminin receptor. Cancer Res. 2004;64:3572–3579. doi: 10.1158/0008-5472.CAN-03-3424. PubMed DOI

Aisenbrey E.A., Murphy W.L. Synthetic alternatives to Matrigel. Nat. Rev. Mater. 2020;5:539–551. doi: 10.1038/s41578-020-0199-8. PubMed DOI PMC

Athukorala S.S., Tran T.S., Balu R., Truong V.K., Chapman J., Dutta N.K., Roy Choudhury N. 3D Printable Electrically Conductive Hydrogel Scaffolds for Biomedical Applications: A Review. Polymers. 2021;13:474. doi: 10.3390/polym13030474. PubMed DOI PMC

Unnikrishnan K., Thomas L.V., Ram Kumar R.M. Advancement of Scaffold-Based 3D Cellular Models in Cancer Tissue Engineering: An Update. Front. Oncol. 2021;11:733652. doi: 10.3389/fonc.2021.733652. PubMed DOI PMC

Ermis M., Falcone N., Roberto de Barros N., Mecwan M., Haghniaz R., Choroomi A., Monirizad M., Lee Y., Song J., Cho H.J., et al. Tunable hybrid hydrogels with multicellular spheroids for modeling desmoplastic pancreatic cancer. Bioact. Mater. 2023;25:360–373. doi: 10.1016/j.bioactmat.2023.02.005. PubMed DOI PMC

Ma B., Wang X., Bove A.M., Simone G. Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role. Front. Cell Dev. Biol. 2020;8:599281. doi: 10.3389/fcell.2020.599281. PubMed DOI PMC

Yan M., Wang L., Wu Y., Lu Y. Three-dimensional highly porous hydrogel scaffold for neural circuit dissection and modulation. Acta Biomater. 2023;157:252–262. doi: 10.1016/j.actbio.2022.12.011. PubMed DOI

Curvello R., Kast V., Abuwarwar M.H., Fletcher A.L., Garnier G., Loessner D. 3D Collagen-Nanocellulose Matrices Model the Tumour Microenvironment of Pancreatic Cancer. Front. Digit. Health. 2021;3:704584. doi: 10.3389/fdgth.2021.704584. PubMed DOI PMC

Khan A.H., Zhou S.P., Moe M., Ortega Quesada B.A., Bajgiran K.R., Lassiter H.R., Dorman J.A., Martin E.C., Pojman J.A., Melvin A.T. Generation of 3D Spheroids Using a Thiol–Acrylate Hydrogel Scaffold to Study Endocrine Response in ER+ Breast Cancer. ACS Biomater. Sci. Eng. 2022;8:3977–3985. doi: 10.1021/acsbiomaterials.2c00491. PubMed DOI PMC

El-Sherbiny I.M., Yacoub M.H. Hydrogel scaffolds for tissue engineering: Progress and challenges. Glob. Cardiol. Sci. Pract. 2013;2013:316–342. doi: 10.5339/gcsp.2013.38. PubMed DOI PMC

Geckil H., Xu F., Zhang X., Moon S., Demirci U. Engineering hydrogels as extracellular matrix mimics. Nanomedicine. 2010;5:469–484. doi: 10.2217/nnm.10.12. PubMed DOI PMC

Kanton S., Paşca S.P. Human assembloids. Development. 2022;149:dev201120. doi: 10.1242/dev.201120. PubMed DOI

Choi J.I., Rim J.H., Jang S.I., Park J.S., Park H., Cho J.H., Lim J.B. The role of Jagged1 as a dynamic switch of cancer cell plasticity in PDAC assembloids. Theranostics. 2022;12:4431–4445. doi: 10.7150/thno.71364. PubMed DOI PMC

Mondadori C., Crippa M., Moretti M., Candrian C., Lopa S., Arrigoni C. Advanced Microfluidic Models of Cancer and Immune Cell Extravasation: A Systematic Review of the Literature. Front. Bioeng. Biotechnol. 2020;8:907. doi: 10.3389/fbioe.2020.00907. PubMed DOI PMC

Dadgar N., Gonzalez-Suarez A.M., Fattahi P., Hou X., Weroha J.S., Gaspar-Maia A., Stybayeva G., Revzin A. A microfluidic platform for cultivating ovarian cancer spheroids and testing their responses to chemotherapies. Microsyst. Nanoeng. 2020;6:93. doi: 10.1038/s41378-020-00201-6. PubMed DOI PMC

Lim W., Park S. A Microfluidic Spheroid Culture Device with a Concentration Gradient Generator for High-Throughput Screening of Drug Efficacy. Molecules. 2018;23:3355. doi: 10.3390/molecules23123355. PubMed DOI PMC

Bradney M.J., Venis S.M., Yang Y., Konieczny S.F., Han B. A Biomimetic Tumor Model of Heterogeneous Invasion in Pancreatic Ductal Adenocarcinoma. Small. 2020;16:e1905500. doi: 10.1002/smll.201905500. PubMed DOI PMC

Sonmez U.M., Cheng Y.-W., Watkins S.C., Roman B.L., Davidson L.A. Endothelial cell polarization and orientation to flow in a novel microfluidic multimodal shear stress generator. Lab Chip. 2020;2:4373–4439. doi: 10.1039/D0LC00738B. PubMed DOI PMC

Beer M., Kuppalu N., Stefanini M., Becker H., Schulz I., Manoli S., Schuette J., Schmees C., Casazza A., Stelzle M., et al. A novel microfluidic 3D platform for culturing pancreatic ductal adenocarcinoma cells: Comparison with in vitro cultures and in vivo xenografts. Sci. Rep. 2017;7:1325. doi: 10.1038/s41598-017-01256-8. PubMed DOI PMC

Sato O., Tsuchikawa T., Kato T., Amaishi Y., Okamoto S., Mineno J., Takeuchi Y., Sasaki K., Nakamura T., Umemoto K., et al. Tumor Growth Suppression of Pancreatic Cancer Orthotopic Xenograft Model by CEA-Targeting CAR-T Cells. Cancers. 2023;15:601. doi: 10.3390/cancers15030601. PubMed DOI PMC

Wu C., Hu B., Wang L., Wu X., Gu H., Dong H., Yan J., Qi Z., Zhang Q., Chen H., et al. Assessment of stromal SCD-induced drug resistance of PDAC using 3D-printed zPDX model chips. iScience. 2023;26:105723. doi: 10.1016/j.isci.2022.105723. PubMed DOI PMC

Mallya K., Gautam S.K., Aithal A., Batra S.K., Jain M. Modeling pancreatic cancer in mice for experimental therapeutics. Biochim. Biophys. Acta Rev. Cancer. 2021;1876:188554. doi: 10.1016/j.bbcan.2021.188554. PubMed DOI PMC

Zeng Z., Wong C.J., Yang L., Ouardaoui N., Li D., Zhang W., Gu S., Zhang Y., Liu Y., Wang X., et al. TISMO: Syngeneic mouse tumor database to model tumor immunity and immunotherapy response. Nucleic Acids Res. 2022;50:D1391–D1397. doi: 10.1093/nar/gkab804. PubMed DOI PMC

Rovithi M., Avan A., Funel N., Leon L.G., Gomez V.E., Wurdinger T., Griffioen A.W., Verheul H.M.W., Giovannetti E. Development of bioluminescent chick chorioallantoic membrane (CAM) models for primary pancreatic cancer cells: A platform for drug testing. Sci. Rep. 2017;7:44686. doi: 10.1038/srep44686. PubMed DOI PMC

Johnson J.I., Decker S., Sausville E.A., Zaharevitz D., Rubinstein L.V., Venditti J.M., Schepartz S., Kalyandrug S., Christian M., Arbuck S., et al. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br. J. Cancer. 2001;84:1424–1431. doi: 10.1054/bjoc.2001.1796. PubMed DOI PMC

Voskoglou-Nomikos T., Pater J.L., Seymour L. Clinical Predictive Value of the in Vitro Cell Line, Human Xenograft, and Mouse Allograft Preclinical Cancer Models. Clin. Cancer Res. 2003;9:4227–4239. PubMed

Garber K. From Human to Mouse and Back: “Tumorgraft” Models Surge in Popularity. JNCI J. Natl. Cancer Inst. 2009;101:6–8. doi: 10.1093/jnci/djn481. PubMed DOI

Bruns C.J., Harbison M.T., Davis D.W., Portera C.A., Tsan R., McConkey D.J., Evans D.B., Abbruzzese J.L., Hicklin D.J., Radinsky R. Epidermal Growth Factor Receptor Blockade with C225 Plus Gemcitabine Results in Regression of Human Pancreatic Carcinoma Growing Orthotopically in Nude Mice by Antiangiogenic Mechanisms. Clin. Cancer Res. 2000;6:1936–1948. PubMed

Philip P.A., Benedetti J., Khorana A.A., Goldman B., Fenoglio-Preiser C.M., Abbruzzese J.L., Blanke C.D., Corless C.L., Wong R., O’Reilly E.M., et al. Phase III Study Comparing Gemcitabine Plus Cetuximab Versus Gemcitabine in Patients with Advanced Pancreatic Adenocarcinoma: Southwest Oncology Group–Directed Intergroup Trial S0205. J. Clin. Oncol. 2010;28:3605–3610. doi: 10.1200/JCO.2009.25.7550. PubMed DOI PMC

Koutsounas I., Giaginis C., Theocharis S. Histone deacetylase inhibitors and pancreatic cancer: Are there any promising clinical trials? World J. Gastroenterol. 2013;19:1173–1181. doi: 10.3748/wjg.v19.i8.1173. PubMed DOI PMC

Mak I.W., Evaniew N., Ghert M. Lost in translation: Animal models and clinical trials in cancer treatment. Am. J. Transl. Res. 2014;6:114–118. PubMed PMC

Van Hemelryk A., Tomljanovic I., Stuurman D., de Ridder C.M.A., Teubel W.J., Erkens-Schulze S., van de Werken H.J.G., van Royen M., Grudniewska M., Jenster G.W., et al. Patient-derived xenografts and organoids recapitulate castration-resistant prostate cancer with sustained androgen receptor signaling. Eur. J. Cancer. 2022;174:S43. doi: 10.1016/S0959-8049(22)00914-5. PubMed DOI PMC

Heinrich M.A., Uboldi I., Kuninty P.R., Ankone M.J.K., van Baarlen J., Zhang Y.S., Jain K., Prakash J. Microarchitectural mimicking of stroma-induced vasculature compression in pancreatic tumors using a 3D engineered model. Bioact. Mater. 2023;22:18–33. doi: 10.1016/j.bioactmat.2022.09.015. PubMed DOI PMC

Miyabayashi K., Baker L.A., Deschênes A., Traub B., Caligiuri G., Plenker D., Alagesan B., Belleau P., Li S., Kendall J., et al. Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes. Cancer Discov. 2020;10:1566–1589. doi: 10.1158/2159-8290.CD-20-0133. PubMed DOI PMC

Boj S.F., Hwang C.-I., Baker L.A., Chio I.I.C., Engle D.D., Corbo V., Jager M., Ponz-Sarvise M., Tiriac H., Spector M.S., et al. Organoid Models of Human and Mouse Ductal Pancreatic Cancer. Cell. 2015;160:324–338. doi: 10.1016/j.cell.2014.12.021. PubMed DOI PMC

Olive K.P., Jacobetz M.A., Davidson C.J., Gopinathan A., McIntyre D., Honess D., Madhu B., Goldgraben M.A., Caldwell M.E., Allard D., et al. Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer. Science. 2009;324:1457–1461. doi: 10.1126/science.1171362. PubMed DOI PMC

Tanaka C., Furihata K., Naganuma S., Ogasawara M., Yoshioka R., Taniguchi H., Furihata M., Taniuchi K. Establishment of a mouse model of pancreatic cancer using human pancreatic cancer cell line S2-013-derived organoid. Hum. Cell Off. J. Hum. Cell Res. Soc. 2022;35:735–744. doi: 10.1007/s13577-022-00684-7. PubMed DOI PMC

Raimondi G., Mato-Berciano A., Pascual-Sabater S., Rovira-Rigau M., Cuatrecasas M., Fondevila C., Sánchez-Cabús S., Begthel H., Boj S.F., Clevers H., et al. Patient-derived pancreatic tumour organoids identify therapeutic responses to oncolytic adenoviruses. EBioMedicine. 2020;56:102786. doi: 10.1016/j.ebiom.2020.102786. PubMed DOI PMC

Le Bras A. Humanized mouse models of drug metabolism. Lab Anim. 2024;53:87. doi: 10.1038/s41684-024-01357-8. PubMed DOI

Gonzalez H., Hagerling C., Werb Z. Roles of the immune system in cancer: From tumor initiation to metastatic progression. Genes. Dev. 2018;32:1267–1284. doi: 10.1101/gad.314617.118. PubMed DOI PMC

Lee S.H., Hu W., Matulay J.T., Silva M.V., Owczarek T.B., Kim K., Chua C.W., Barlow L.J., Kandoth C., Williams A.B., et al. Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer. Cell. 2018;173:515–528.e517. doi: 10.1016/j.cell.2018.03.017. PubMed DOI PMC

Edgar R.D., Perrone F., Foster A.R., Payne F., Lewis S., Nayak K.M., Kraiczy J., Cenier A., Torrente F., Salvestrini C., et al. Culture-Associated DNA Methylation Changes Impact on Cellular Function of Human Intestinal Organoids. Cell Mol. Gastroenterol. Hepatol. 2022;14:1295–1310. doi: 10.1016/j.jcmgh.2022.08.008. PubMed DOI PMC

Fang Z., Li P., Du F., Shang L., Li L. The role of organoids in cancer research. Exp. Hematol. Oncol. 2023;12:69. doi: 10.1186/s40164-023-00433-y. PubMed DOI PMC

Peng Z., Lv X., Sun H., Zhao L., Huang S. 3D tumor cultures for drug resistance and screening development in clinical applications. Mol. Cancer. 2025;24:93. doi: 10.1186/s12943-025-02281-2. PubMed DOI PMC

Abdolahi S., Ghazvinian Z., Muhammadnejad S., Saleh M., Asadzadeh Aghdaei H., Baghaei K. Patient-derived xenograft (PDX) models, applications and challenges in cancer research. J. Transl. Med. 2022;20:206. doi: 10.1186/s12967-022-03405-8. PubMed DOI PMC

Seppälä T.T., Zimmerman J.W., Sereni E., Plenker D., Suri R., Rozich N., Blair A., Thomas D.L., Teinor J., Javed A., et al. Patient-derived Organoid Pharmacotyping is a Clinically Tractable Strategy for Precision Medicine in Pancreatic Cancer. Ann. Surg. 2020;272:427–435. doi: 10.1097/SLA.0000000000004200. PubMed DOI PMC

Magouliotis D., Dimas K., Sakellaridis N., Ioannou M., Zacharouli K., Ntalagiorgos A., Fergadi M., Zacharoulis D. Development of an Orthotopic Pancreatic Ductal Adenocarcinoma (PDAC) Patient Derived Xenografts (PDX) Preclinical Model and Characterization of Aquaporin 7 (AQP7) Expression. HPB. 2022;24:S304. doi: 10.1016/j.hpb.2022.05.642. DOI

Wu L., Zhang F., Chen X., Wan J., Wang Y., Li T., Wang H. Self-Assembled Gemcitabine Prodrug Nanoparticles Show Enhanced Efficacy against Patient-Derived Pancreatic Ductal Adenocarcinoma. ACS Appl. Mater. Interfaces. 2020;12:3327–3340. doi: 10.1021/acsami.9b16209. PubMed DOI

Garcia P.L., Miller A.L., Kreitzburg K.M., Council L.N., Gamblin T.L., Christein J.D., Heslin M.J., Arnoletti J.P., Richardson J.H., Chen D., et al. The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene. 2016;35:833–845. doi: 10.1038/onc.2015.126. PubMed DOI PMC

Zanella E.R., Grassi E., Trusolino L. Towards precision oncology with patient-derived xenografts. Nat. Rev. Clin. Oncol. 2022;19:719–732. doi: 10.1038/s41571-022-00682-6. PubMed DOI

Delitto D., Pham K., Vlada A.C., Sarosi G.A., Thomas R.M., Behrns K.E., Liu C., Hughes S.J., Wallet S.M., Trevino J.G. Patient-Derived Xenograft Models for Pancreatic Adenocarcinoma Demonstrate Retention of Tumor Morphology through Incorporation of Murine Stromal Elements. Am. J. Pathol. 2015;185:1297–1303. doi: 10.1016/j.ajpath.2015.01.016. PubMed DOI PMC

Yoshida G.J. Applications of patient-derived tumor xenograft models and tumor organoids. J. Hematol. Oncol. 2020;13:4–16. doi: 10.1186/s13045-019-0829-z. PubMed DOI PMC

Liu X., Xin Z., Wang K. Patient-derived xenograft model in colorectal cancer basic and translational research. Anim. Models Exp. Med. 2023;6:26–40. doi: 10.1002/ame2.12299. PubMed DOI PMC

De La Rochere P., Guil-Luna S., Decaudin D., Azar G., Sidhu S.S., Piaggio E. Humanized Mice for the Study of Immuno-Oncology. Trends Immunol. 2018;39:748–763. doi: 10.1016/j.it.2018.07.001. PubMed DOI

Tentler J.J., Tan A.C., Weekes C.D., Jimeno A., Leong S., Pitts T.M., Arcaroli J.J., Messersmith W.A., Eckhardt S.G. Patient-derived tumour xenografts as models for oncology drug development. Nat. Rev. Clin. Oncol. 2012;9:338–350. doi: 10.1038/nrclinonc.2012.61. PubMed DOI PMC

Ekins S., Mestres J., Testa B. In silico pharmacology for drug discovery: Methods for virtual ligand screening and profiling. Br. J. Pharmacol. 2007;152:9–20. doi: 10.1038/sj.bjp.0707305. PubMed DOI PMC

Güven E. Gene Expression Characteristics of Tumor and Adjacent Non-Tumor Tissues of Pancreatic Ductal Adenocarcinoma (PDAC) In-Silico. Iran. J. Biotechnol. 2022;20:e3092. doi: 10.30498/ijb.2021.292558.3092. PubMed DOI PMC

Zaccagnino A., Pilarsky C., Tawfik D., Sebens S., Trauzold A., Novak I., Schwab A., Kalthoff H. In silico analysis of the transportome in human pancreatic ductal adenocarcinoma. Eur. Biophys. J. 2016;45:749–763. doi: 10.1007/s00249-016-1171-9. PubMed DOI

Jain A., Bhardwaj V. Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities. World J. Gastroenterol. 2021;27:6527–6550. doi: 10.3748/wjg.v27.i39.6527. PubMed DOI PMC

Broekgaarden M., Weijer R., van Gulik T.M., Hamblin M.R., Heger M. Tumor cell survival pathways activated by photodynamic therapy: A molecular basis for pharmacological inhibition strategies. Cancer Metastasis Rev. 2015;34:643–690. doi: 10.1007/s10555-015-9588-7. PubMed DOI PMC

Yanovsky R.L., Bartenstein D.W., Rogers G.S., Isakoff S.J., Chen S.T. Photodynamic therapy for solid tumors: A review of the literature. Photodermatol. Photoimmunol. Photomed. 2019;35:295–303. doi: 10.1111/phpp.12489. PubMed DOI

Schuitmaker J.J., Baas P., van Leengoed H.L., van der Meulen F.W., Star W.M., van Zandwijk N. Photodynamic therapy: A promising new modality for the treatment of cancer. J. Photochem. Photobiol. B. 1996;34:3–12. doi: 10.1016/1011-1344(96)07342-3. PubMed DOI

Kim T.E., Chang J.E. Recent Studies in Photodynamic Therapy for Cancer Treatment: From Basic Research to Clinical Trials. Pharmaceutics. 2023;15:2257. doi: 10.3390/pharmaceutics15092257. PubMed DOI PMC

Reiniers M.J., van Golen R.F., Bonnet S., Broekgaarden M., van Gulik T.M., Egmond M.R., Heger M. Preparation and Practical Applications of 2′,7′-Dichlorodihydrofluorescein in Redox Assays. Anal. Chem. 2017;89:3853–3857. doi: 10.1021/acs.analchem.7b00043. PubMed DOI PMC

Broekgaarden M., de Kroon A.I., Gulik T.M., Heger M. Development and in vitro proof-of-concept of interstitially targeted zinc-phthalocyanine liposomes for photodynamic therapy. Curr. Med. Chem. 2014;21:377–391. doi: 10.2174/09298673113209990211. PubMed DOI

Hsieh Y.J., Chien K.Y., Yang I.F., Lee I.N., Wu C.C., Huang T.Y., Yu J.S. Oxidation of protein-bound methionine in Photofrin-photodynamic therapy-treated human tumor cells explored by methionine-containing peptide enrichment and quantitative proteomics approach. Sci. Rep. 2017;7:1370. doi: 10.1038/s41598-017-01409-9. PubMed DOI PMC

Sakharov D.V., Elstak E.D., Chernyak B., Wirtz K.W. Prolonged lipid oxidation after photodynamic treatment. Study with oxidation-sensitive probe C11-BODIPY581/591. FEBS Lett. 2005;579:1255–1260. doi: 10.1016/j.febslet.2005.01.024. PubMed DOI

Kanamori T., Kaneko S., Hamamoto K., Yuasa H. Mapping the diffusion pattern of (1)O(2) along DNA duplex by guanine photooxidation with an appended biphenyl photosensitizer. Sci. Rep. 2023;13:288. doi: 10.1038/s41598-023-27526-2. PubMed DOI PMC

Weijer R., Broekgaarden M., Kos M., van Vught R., Rauws E.A., Breukink E.J., van Gulik T.M., Storm G., Heger M. Enhancing photodynamic therapy of refractory solid cancers: Combining second-generation photosensitizers with multi-targeted liposomal delivery. J. Photochem. Photobiol. C. 2015;23:103–131. doi: 10.1016/j.jphotochemrev.2015.05.002. DOI

Castano A.P., Demidova T.N., Hamblin M.R. Mechanisms in photodynamic therapy: Part two-cellular signaling, cell metabolism and modes of cell death. Photodiagnosis Photodyn. Ther. 2005;2:1–23. doi: 10.1016/S1572-1000(05)00030-X. PubMed DOI PMC

Weijer R., Clavier S., Zaal E.A., Pijls M.M., van Kooten R.T., Vermaas K., Leen R., Jongejan A., Moerland P.D., van Kampen A.H., et al. Multi-OMIC profiling of survival and metabolic signaling networks in cells subjected to photodynamic therapy. Cell Mol. Life Sci. 2017;74:1133–1151. doi: 10.1007/s00018-016-2401-0. PubMed DOI PMC

Dias L.M., Sharifi F., de Keijzer M.J., Mesquita B., Desclos E., Kochan J.A., de Klerk D.J., Ernst D., de Haan L.R., Franchi L.P., et al. Attritional evaluation of lipophilic and hydrophilic metallated phthalocyanines for oncological photodynamic therapy. J. Photochem. Photobiol. B. 2021;216:112146. doi: 10.1016/j.jphotobiol.2021.112146. PubMed DOI

Mishchenko T., Balalaeva I., Gorokhova A., Vedunova M., Krysko D.V. Which cell death modality wins the contest for photodynamic therapy of cancer? Cell Death Dis. 2022;13:455. doi: 10.1038/s41419-022-04851-4. PubMed DOI PMC

Alzeibak R., Mishchenko T.A., Shilyagina N.Y., Balalaeva I.V., Vedunova M.V., Krysko D.V. Targeting immunogenic cancer cell death by photodynamic therapy: Past, present and future. J. Immunother. Cancer. 2021;9:e001926. doi: 10.1136/jitc-2020-001926. PubMed DOI PMC

Behrend L., Henderson G., Zwacka R.M. Reactive oxygen species in oncogenic transformation. Biochem. Soc. Trans. 2003;31:1441–1444. doi: 10.1042/bst0311441. PubMed DOI

Hu Y., Rosen D.G., Zhou Y., Feng L., Yang G., Liu J., Huang P. Mitochondrial manganese-superoxide dismutase expression in ovarian cancer: Role in cell proliferation and response to oxidative stress. J. Biol. Chem. 2005;280:39485–39492. doi: 10.1074/jbc.M503296200. PubMed DOI

Trachootham D., Lu W., Ogasawara M.A., Nilsa R.D., Huang P. Redox regulation of cell survival. Antioxid. Redox Signal. 2008;10:1343–1374. doi: 10.1089/ars.2007.1957. PubMed DOI PMC

Ushio-Fukai M., Nakamura Y. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett. 2008;266:37–52. doi: 10.1016/j.canlet.2008.02.044. PubMed DOI PMC

Wu W.S. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev. 2006;25:695–705. doi: 10.1007/s10555-006-9037-8. PubMed DOI

Nishikawa M. Reactive oxygen species in tumor metastasis. Cancer Lett. 2008;266:53–59. doi: 10.1016/j.canlet.2008.02.031. PubMed DOI

Arfin S., Jha N.K., Jha S.K., Kesari K.K., Ruokolainen J., Roychoudhury S., Rathi B., Kumar D. Oxidative Stress in Cancer Cell Metabolism. Antioxidants. 2021;10:642. doi: 10.3390/antiox10050642. PubMed DOI PMC

Trachootham D., Alexandre J., Huang P. Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach? Nat. Rev. Drug Discov. 2009;8:579–591. doi: 10.1038/nrd2803. PubMed DOI

Zhou Z., Song J., Nie L., Chen X. Reactive oxygen species generating systems meeting challenges of photodynamic cancer therapy. Chem. Soc. Rev. 2016;45:6597–6626. doi: 10.1039/C6CS00271D. PubMed DOI PMC

Weijer R., Broekgaarden M., van Golen R.F., Bulle E., Nieuwenhuis E., Jongejan A., Moerland P.D., van Kampen A.H., van Gulik T.M., Heger M. Low-power photodynamic therapy induces survival signaling in perihilar cholangiocarcinoma cells. BMC Cancer. 2015;15:1014. doi: 10.1186/s12885-015-1994-2. PubMed DOI PMC

De Silva P., Bano S., Pogue B.W., Wang K.K., Maytin E.V., Hasan T. Photodynamic priming with triple-receptor targeted nanoconjugates that trigger T cell-mediated immune responses in a 3D in vitro heterocellular model of pancreatic cancer. Nanophotonics. 2021;10:3199–3214. doi: 10.1515/nanoph-2021-0304. PubMed DOI PMC

Seshadri M., Spernyak J.A., Mazurchuk R., Camacho S.H., Oseroff A.R., Cheney R.T., Bellnier D.A. Tumor vascular response to photodynamic therapy and the antivascular agent 5,6-dimethylxanthenone-4-acetic acid: Implications for combination therapy. Clin. Cancer Res. 2005;11:4241–4250. doi: 10.1158/1078-0432.CCR-04-2703. PubMed DOI

Wang W., Moriyama L.T., Bagnato V.S. Photodynamic therapy induced vascular damage: An overview of experimental PDT. Laser Phys. Lett. 2013;10:023001. doi: 10.1088/1612-2011/10/2/023001. DOI

Bano S., Alburquerque J.Q., Roberts H.J., Pang S., Huang H.C., Hasan T. Minocycline and photodynamic priming significantly improve chemotherapy efficacy in heterotypic spheroids of pancreatic ductal adenocarcinoma. J. Photochem. Photobiol. B. 2024;255:112910. doi: 10.1016/j.jphotobiol.2024.112910. PubMed DOI PMC

Kleinovink J.W., van Driel P.B., Snoeks T.J., Prokopi N., Fransen M.F., Cruz L.J., Mezzanotte L., Chan A., Lowik C.W., Ossendorp F. Combination of Photodynamic Therapy and Specific Immunotherapy Efficiently Eradicates Established Tumors. Clin. Cancer Res. 2016;22:1459–1468. doi: 10.1158/1078-0432.CCR-15-0515. PubMed DOI

Schroder T., Chen I.W., Sperling M., Bell R.H., Jr., Brackett K., Joffe S.N. Hematoporphyrin derivative uptake and photodynamic therapy in pancreatic carcinoma. J. Surg. Oncol. 1988;38:4–9. doi: 10.1002/jso.2930380103. PubMed DOI

Chatlani P.T., Nuutinen P.J., Toda N., Barr H., MacRobert A.J., Bedwell J., Bown S.G. Selective necrosis in hamster pancreatic tumours using photodynamic therapy with phthalocyanine photosensitization. Br. J. Surg. 1992;79:786–790. doi: 10.1002/bjs.1800790826. PubMed DOI

Mikvy P., Messman H., MacRobert A.J., Pauer M., Sams V.R., Davies C.L., Stewart J.C., Bown S.G. Photodynamic therapy of a transplanted pancreatic cancer model using meta-tetrahydroxyphenylchlorin (mTHPC) Br. J. Cancer. 1997;76:713–718. doi: 10.1038/bjc.1997.451. PubMed DOI PMC

Hajri A., Coffy S., Vallat F., Evrard S., Marescaux J., Aprahamian M. Human pancreatic carcinoma cells are sensitive to photodynamic therapy in vitro and in vivo. Br. J. Surg. 1999;86:899–906. doi: 10.1046/j.1365-2168.1999.01132.x. PubMed DOI

Sun F., Zhu Q., Li T., Saeed M., Xu Z., Zhong F., Song R., Huai M., Zheng M., Xie C., et al. Regulating Glucose Metabolism with Prodrug Nanoparticles for Promoting Photoimmunotherapy of Pancreatic Cancer. Adv. Sci. 2021;8:2002746. doi: 10.1002/advs.202002746. PubMed DOI PMC

De Silva P., Saad M.A., Camargo A.P., Swain J., Palanasami A., Obaid G., Shetty S., Hasan T. Abstract A17: Enhanced immune infiltration and antitumor immune reactivity in response to optical priming in pancreatic cancer. Cancer Immunol. Res. 2020;8:A17. doi: 10.1158/2326-6074.TUMIMM19-A17. DOI

Huang H.C., Rizvi I., Liu J., Anbil S., Kalra A., Lee H., Baglo Y., Paz N., Hayden D., Pereira S., et al. Photodynamic Priming Mitigates Chemotherapeutic Selection Pressures and Improves Drug Delivery. Cancer Res. 2018;78:558–571. doi: 10.1158/0008-5472.CAN-17-1700. PubMed DOI PMC

Weijer R., Broekgaarden M., Krekorian M., Alles L.K., van Wijk A.C., Mackaaij C., Verheij J., van der Wal A.C., van Gulik T.M., Storm G., et al. Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy. Oncotarget. 2016;7:3341–3356. doi: 10.18632/oncotarget.6490. PubMed DOI PMC

Broekgaarden M., Weijer R., Krekorian M., van den Ijssel B., Kos M., Alles L.K., van Wijk A.C., Bikadi Z., Hazai E., van Gulik T.M., et al. Inhibition of hypoxia-inducible factor 1 with acriflavine sensitizes hypoxic tumor cells to photodynamic therapy with zinc phthalocyanine-encapsulating cationic liposomes. Nano Res. 2016;9:1639–1662. doi: 10.1007/s12274-016-1059-0. DOI

de Keijzer M.J., de Klerk D.J., de Haan L.R., van Kooten R.T., Franchi L.P., Dias L.M., Kleijn T.G., van Doorn D.J., Heger M., on behalf of the Photodynamic Therapy Study Group Inhibition of the HIF-1 Survival Pathway as a Strategy to Augment Photodynamic Therapy Efficacy. Methods Mol. Biol. 2022;2451:285–403. doi: 10.1007/978-1-0716-2099-1_19. PubMed DOI

Conte M., Cauda V. Multimodal Therapies against Pancreatic Ductal Adenocarcinoma: A Review on Synergistic Approaches toward Ultimate Nanomedicine Treatments. Adv. Ther. 2022;5:2200079. doi: 10.1002/adtp.202200079. DOI

Anbil S., Pigula M., Huang H.C., Mallidi S., Broekgaarden M., Baglo Y., De Silva P., Simeone D.M., Mino-Kenudson M., Maytin E.V., et al. Vitamin D Receptor Activation and Photodynamic Priming Enables Durable Low-dose Chemotherapy. Mol. Cancer Ther. 2020;19:1308–1319. doi: 10.1158/1535-7163.MCT-19-0791. PubMed DOI PMC

Obaid G., Bano S., Mallidi S., Broekgaarden M., Kuriakose J., Silber Z., Bulin A.L., Wang Y., Mai Z., Jin W., et al. Impacting Pancreatic Cancer Therapy in Heterotypic in Vitro Organoids and in Vivo Tumors with Specificity-Tuned, NIR-Activable Photoimmunonanoconjugates: Towards Conquering Desmoplasia? Nano Lett. 2019;19:7573–7587. doi: 10.1021/acs.nanolett.9b00859. PubMed DOI PMC

Obaid G., Bano S., Thomsen H., Callaghan S., Shah N., Swain J.W.R., Jin W., Ding X., Cameron C.G., McFarland S.A., et al. Remediating Desmoplasia with EGFR-Targeted Photoactivable Multi-Inhibitor Liposomes Doubles Overall Survival in Pancreatic Cancer. Adv. Sci. 2022;9:e2104594. doi: 10.1002/advs.202104594. PubMed DOI PMC

Grunwald B.T., Devisme A., Andrieux G., Vyas F., Aliar K., McCloskey C.W., Macklin A., Jang G.H., Denroche R., Romero J.M., et al. Spatially confined sub-tumor microenvironments in pancreatic cancer. Cell. 2021;184:5577–5592.e18. doi: 10.1016/j.cell.2021.09.022. PubMed DOI

Bailey P., Zhou X., An J., Peccerella T., Hu K., Springfeld C., Buchler M., Neoptolemos J.P. Refining the Treatment of Pancreatic Cancer From Big Data to Improved Individual Survival. Function. 2023;4:zqad011. doi: 10.1093/function/zqad011. PubMed DOI PMC

Karimnia V., Rizvi I., Slack F.J., Celli J.P. Photodestruction of Stromal Fibroblasts Enhances Tumor Response to PDT in 3D Pancreatic Cancer Coculture Models. Photochem. Photobiol. 2021;97:416–426. doi: 10.1111/php.13339. PubMed DOI PMC

Tan P., Cai H., Wei Q., Tang X., Zhang Q., Kopytynski M., Yang J., Yi Y., Zhang H., Gong Q., et al. Enhanced chemo-photodynamic therapy of an enzyme-responsive prodrug in bladder cancer patient-derived xenograft models. Biomaterials. 2021;277:121061. doi: 10.1016/j.biomaterials.2021.121061. PubMed DOI

Murayama T., Gotoh N. Patient-Derived Xenograft Models of Breast Cancer and Their Application. Cells. 2019;8:621. doi: 10.3390/cells8060621. PubMed DOI PMC

Chitrangi S., Vaity P., Jamdar A., Bhatt S. Patient-derived organoids for precision oncology: A platform to facilitate clinical decision making. BMC Cancer. 2023;23:689. doi: 10.1186/s12885-023-11078-9. PubMed DOI PMC

Bubin R., Uljanovs R., Strumfa I. Cancer Stem Cells in Pancreatic Ductal Adenocarcinoma. Int. J. Mol. Sci. 2023;24:7030. doi: 10.3390/ijms24087030. PubMed DOI PMC

Gurung P., Lim J., Shrestha R., Kim Y.W. Chlorin e6-associated photodynamic therapy enhances abscopal antitumor effects via inhibition of PD-1/PD-L1 immune checkpoint. Sci. Rep. 2023;13:4647. doi: 10.1038/s41598-023-30256-0. PubMed DOI PMC

Lou J., Aragaki M., Bernards N., Chee T., Gregor A., Hiraishi Y., Ishiwata T., Leung C., Ding L., Kitazawa S., et al. Repeated photodynamic therapy mediates the abscopal effect through multiple innate and adaptive immune responses with and without immune checkpoint therapy. Biomaterials. 2023;292:121918. doi: 10.1016/j.biomaterials.2022.121918. PubMed DOI

Quilbe A., Morales O., Baydoun M., Kumar A., Mustapha R., Murakami T., Leroux B., de Schutter C., Thecua E., Ziane L., et al. An Efficient Photodynamic Therapy Treatment for Human Pancreatic Adenocarcinoma. J. Clin. Med. 2020;9:192. doi: 10.3390/jcm9010192. PubMed DOI PMC

Wang Y., Wang H., Zhou L., Lu J., Jiang B., Liu C., Guo J. Photodynamic therapy of pancreatic cancer: Where have we come from and where are we going? Photodiagnosis Photodyn. Ther. 2020;31:101876. doi: 10.1016/j.pdpdt.2020.101876. PubMed DOI

Dorst D.N., Smeets E.M.M., Klein C., Frielink C., Geijs D., Trajkovic-Arsic M., Cheung P.F.Y., Stommel M.W.J., Gotthardt M., Siveke J.T., et al. Fibroblast Activation Protein-Targeted Photodynamic Therapy of Cancer-Associated Fibroblasts in Murine Models for Pancreatic Ductal Adenocarcinoma. Mol. Pharm. 2023;20:4319–4330. doi: 10.1021/acs.molpharmaceut.3c00453. PubMed DOI PMC

Tomas-Bort E., Kieler M., Sharma S., Candido J.B., Loessner D. 3D approaches to model the tumor microenvironment of pancreatic cancer. Theranostics. 2020;10:5074–5089. doi: 10.7150/thno.42441. PubMed DOI PMC

Foglizzo V., Cocco E., Marchio S. Advanced Cellular Models for Preclinical Drug Testing: From 2D Cultures to Organ-on-a-Chip Technology. Cancers. 2022;14:3692. doi: 10.3390/cancers14153692. PubMed DOI PMC

Pinto B., Henriques A.C., Silva P.M.A., Bousbaa H. Three-Dimensional Spheroids as In Vitro Preclinical Models for Cancer Research. Pharmaceutics. 2020;12:1186. doi: 10.3390/pharmaceutics12121186. PubMed DOI PMC

Hubrecht R.C., Carter E. The 3Rs and Humane Experimental Technique: Implementing Change. Animals. 2019;9:754. doi: 10.3390/ani9100754. PubMed DOI PMC

Saad M.A., Zhung W., Stanley M.E., Formica S., Grimaldo-Garcia S., Obaid G., Hasan T. Photoimmunotherapy Retains Its Anti-Tumor Efficacy with Increasing Stromal Content in Heterotypic Pancreatic Cancer Spheroids. Mol. Pharm. 2022;19:2549–2563. doi: 10.1021/acs.molpharmaceut.2c00260. PubMed DOI PMC

Bulin A.L., Broekgaarden M., Simeone D., Hasan T. Low dose photodynamic therapy harmonizes with radiation therapy to induce beneficial effects on pancreatic heterocellular spheroids. Oncotarget. 2019;10:2625–2643. doi: 10.18632/oncotarget.26780. PubMed DOI PMC

Broekgaarden M., Alkhateeb A., Bano S., Bulin A.L., Obaid G., Rizvi I., Hasan T. Cabozantinib Inhibits Photodynamic Therapy-Induced Auto- and Paracrine MET Signaling in Heterotypic Pancreatic Microtumors. Cancers. 2020;12:1401. doi: 10.3390/cancers12061401. PubMed DOI PMC

Hughes C.S., Postovit L.M., Lajoie G.A. Matrigel: A complex protein mixture required for optimal growth of cell culture. Proteomics. 2010;10:1886–1890. doi: 10.1002/pmic.200900758. PubMed DOI

Benton G., George J., Kleinman H.K., Arnaoutova I.P. Advancing science and technology via 3D culture on basement membrane matrix. J. Cell Physiol. 2009;221:18–25. doi: 10.1002/jcp.21832. PubMed DOI

Kalluri R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer. 2016;16:582–598. doi: 10.1038/nrc.2016.73. PubMed DOI

Hayes J.D., Dinkova-Kostova A.T., Tew K.D. Oxidative Stress in Cancer. Cancer Cell. 2020;38:167–197. doi: 10.1016/j.ccell.2020.06.001. PubMed DOI PMC

Pervaiz S., Clement M.V. Tumor intracellular redox status and drug resistance--serendipity or a causal relationship? Curr. Pharm. Des. 2004;10:1969–1977. doi: 10.2174/1381612043384411. PubMed DOI

Onodera Y., Teramura T., Takehara T., Shigi K., Fukuda K. Reactive oxygen species induce Cox-2 expression via TAK1 activation in synovial fibroblast cells. FEBS Open Bio. 2015;5:492–501. doi: 10.1016/j.fob.2015.06.001. PubMed DOI PMC

Chiang S.K., Chen S.E., Chang L.C. The Role of HO-1 and Its Crosstalk with Oxidative Stress in Cancer Cell Survival. Cells. 2021;10:2401. doi: 10.3390/cells10092401. PubMed DOI PMC

Fontaine E. Metformin-Induced Mitochondrial Complex I Inhibition: Facts, Uncertainties, and Consequences. Front. Endocrinol. 2018;9:753. doi: 10.3389/fendo.2018.00753. PubMed DOI PMC

de Haan L.R., Reiniers M.J., Reeskamp L.F., Belkouz A., Ao L., Cheng S., Ding B., van Golen R.F., Heger M. Experimental Conditions That Influence the Utility of 2′7′-Dichlorodihydrofluorescein Diacetate (DCFH(2)-DA) as a Fluorogenic Biosensor for Mitochondrial Redox Status. Antioxidants. 2022;11:1424. doi: 10.3390/antiox11081424. PubMed DOI PMC

Broekgaarden M., Bulin A.L., Frederick J., Mai Z., Hasan T. Tracking Photodynamic- and Chemotherapy-Induced Redox-State Perturbations in 3D Culture Models of Pancreatic Cancer: A Tool for Identifying Therapy-Induced Metabolic Changes. J. Clin. Med. 2019;8:1399. doi: 10.3390/jcm8091399. PubMed DOI PMC

Carigga Gutierrez N.M., Le Clainche T., Coll J.L., Sancey L., Broekgaarden M. Generating Large Numbers of Pancreatic Microtumors on Alginate-Gelatin Hydrogels for Quantitative Imaging of Tumor Growth and Photodynamic Therapy Optimization. Methods Mol. Biol. 2022;2451:91–105. doi: 10.1007/978-1-0716-2099-1_8. PubMed DOI

Cramer G.M., Jones D.P., El-Hamidi H., Celli J.P. ECM Composition and Rheology Regulate Growth, Motility, and Response to Photodynamic Therapy in 3D Models of Pancreatic Ductal Adenocarcinoma. Mol. Cancer Res. 2017;15:15–25. doi: 10.1158/1541-7786.MCR-16-0260. PubMed DOI PMC

Jafari R., Cramer G.M., Celli J.P. Modulation of Extracellular Matrix Rigidity Via Riboflavin-mediated Photocrosslinking Regulates Invasive Motility and Treatment Response in a 3D Pancreatic Tumor Model. Photochem. Photobiol. 2020;96:365–372. doi: 10.1111/php.13191. PubMed DOI PMC

Andersen T., Auk-Emblem P., Dornish M. 3D Cell Culture in Alginate Hydrogels. Microarrays. 2015;4:133–161. doi: 10.3390/microarrays4020133. PubMed DOI PMC

Abdelrahim A.A., Hong S., Song J.M. Integrative In Situ Photodynamic Therapy-Induced Cell Death Measurement of 3D-Bioprinted MCF-7 Tumor Spheroids. Anal. Chem. 2022;94:13936–13943. doi: 10.1021/acs.analchem.2c03022. PubMed DOI

Biffi G., Oni T.E., Spielman B., Hao Y., Elyada E., Park Y., Preall J., Tuveson D.A. IL1-Induced JAK/STAT Signaling Is Antagonized by TGFbeta to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancer Discov. 2019;9:282–301. doi: 10.1158/2159-8290.CD-18-0710. PubMed DOI PMC

Lehnert L., Trost H., Schmiegel W., Roder C., Kalthoff H. Hollow-spheres: A new model for analyses of differentiation of pancreatic duct epithelial cells. Ann. N. Y. Acad. Sci. 1999;880:83–93. doi: 10.1111/j.1749-6632.1999.tb09512.x. PubMed DOI

Sipos B., Moser S., Kalthoff H., Torok V., Lohr M., Kloppel G. A comprehensive characterization of pancreatic ductal carcinoma cell lines: Towards the establishment of an in vitro research platform. Virchows Arch. 2003;442:444–452. doi: 10.1007/s00428-003-0784-4. PubMed DOI

Winterhoff B.J., Arlt A., Duttmann A., Ungefroren H., Schafer H., Kalthoff H., Kruse M.L. Characterisation of FAP-1 expression and CD95 mediated apoptosis in the A818-6 pancreatic adenocarcinoma differentiation system. Differentiation. 2012;83:148–157. doi: 10.1016/j.diff.2011.11.013. PubMed DOI

Algarni A., Greenman J., Madden L.A. PO-48—Assessment of the procoagulant potential state of tumour-MP in cancer patients. Thromb. Res. 2016;140((Suppl. 1)):S194. doi: 10.1016/S0049-3848(16)30181-5. PubMed DOI

Lee W.T., Lee J., Kim H., Nguyen N.T., Lee E.S., Oh K.T., Choi H.G., Youn Y.S. Photoreactive-proton-generating hyaluronidase/albumin nanoparticles-loaded PEG-hydrogel enhances antitumor efficacy and disruption of the hyaluronic acid extracellular matrix in AsPC-1 tumors. Mater. Today Bio. 2021;12:100164. doi: 10.1016/j.mtbio.2021.100164. PubMed DOI PMC

Yang J., Zhang Z., Zhang Y., Ni X., Zhang G., Cui X., Liu M., Xu C., Zhang Q., Zhu H., et al. ZIP4 Promotes Muscle Wasting and Cachexia in Mice with Orthotopic Pancreatic Tumors by Stimulating RAB27B-Regulated Release of Extracellular Vesicles From Cancer Cells. Gastroenterology. 2019;156:722–734.e726. doi: 10.1053/j.gastro.2018.10.026. PubMed DOI PMC

Hye Jeong J., Park S., Lee S., Kim Y., Kyong Shim I., Jeong S.Y., Kyung Choi E., Kim J., Jun E. Orthotopic model of pancreatic cancer using CD34+ humanized mice and generation of tumor organoids from humanized tumors. Int. Immunopharmacol. 2023;121:110451. doi: 10.1016/j.intimp.2023.110451. PubMed DOI

Er O., Tuncel A., Ocakoglu K., Ince M., Kolatan E.H., Yilmaz O., Aktas S., Yurt F. Radiolabeling, In Vitro Cell Uptake, and In Vivo Photodynamic Therapy Potential of Targeted Mesoporous Silica Nanoparticles Containing Zinc Phthalocyanine. Mol. Pharm. 2020;17:2648–2659. doi: 10.1021/acs.molpharmaceut.0c00331. PubMed DOI

Samkoe K.S., Chen A., Rizvi I., O’Hara J.A., Hoopes P.J., Pereira S.P., Hasan T., Pogue B.W. Imaging tumor variation in response to photodynamic therapy in pancreatic cancer xenograft models. Int. J. Radiat. Oncol. Biol. Phys. 2010;76:251–259. doi: 10.1016/j.ijrobp.2009.08.041. PubMed DOI PMC

Yu L.S., Jhunjhunwala M., Hong S.Y., Yu L.Y., Lin W.R., Chen C.S. Tissue Architecture Influences the Biological Effectiveness of Boron Neutron Capture Therapy in In Vitro/In Silico Three-Dimensional Self-Assembly Cell Models of Pancreatic Cancers. Cancers. 2021;13:4058. doi: 10.3390/cancers13164058. PubMed DOI PMC

Karnevi E., Rosendahl A.H., Hilmersson K.S., Saleem M.A., Andersson R. Impact by pancreatic stellate cells on epithelial-mesenchymal transition and pancreatic cancer cell invasion: Adding a third dimension in vitro. Exp. Cell Res. 2016;346:206–215. doi: 10.1016/j.yexcr.2016.07.017. PubMed DOI

Jhaveri A.V., Zhou L., Ralff M.D., Lee Y.S., Navaraj A., Carneiro B.A., Safran H., Prabhu V.V., Ross E.A., Lee S., et al. Combination of ONC201 and TLY012 induces selective, synergistic apoptosis in vitro and significantly delays PDAC xenograft growth in vivo. Cancer Biol. Ther. 2021;22:607–618. doi: 10.1080/15384047.2021.1976567. PubMed DOI PMC

Lee J., Han S., Thapa Magar T.B., Gurung P., Lee J., Seong D., Park S., Kim Y.W., Jeon M., Kim J. Efficient Assessment of Tumor Vascular Shutdown by Photodynamic Therapy on Orthotopic Pancreatic Cancer Using High-Speed Wide-Field Waterproof Galvanometer Scanner Photoacoustic Microscopy. Int. J. Mol. Sci. 2024;25:3457. doi: 10.3390/ijms25063457. PubMed DOI PMC

Froeling F.E., Feig C., Chelala C., Dobson R., Mein C.E., Tuveson D.A., Clevers H., Hart I.R., Kocher H.M. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-beta-catenin signaling to slow tumor progression. Gastroenterology. 2011;141:1486–1497.e14. doi: 10.1053/j.gastro.2011.06.047. PubMed DOI

Kuroda Y., Oda T., Shimomura O., Hashimoto S., Akashi Y., Miyazaki Y., Furuya K., Furuta T., Nakahashi H., Louphrasitthiphol P., et al. Lectin-based phototherapy targeting cell surface glycans for pancreatic cancer. Int. J. Cancer. 2023;152:1425–1437. doi: 10.1002/ijc.34362. PubMed DOI PMC

Benzing C., Lam H., Tsang C.M., Rimmer A., Arroyo-Berdugo Y., Calle Y., Wells C.M. TIMP-2 secreted by monocyte-like cells is a potent suppressor of invadopodia formation in pancreatic cancer cells. BMC Cancer. 2019;19:1214. doi: 10.1186/s12885-019-6429-z. PubMed DOI PMC

Shapoval O., Vetvicka D., Patsula V., Engstova H., Kockova O., Konefal M., Kabesova M., Horak D. Temoporfin-Conjugated Upconversion Nanoparticles for NIR-Induced Photodynamic Therapy: Studies with Pancreatic Adenocarcinoma Cells In Vitro and In Vivo. Pharmaceutics. 2023;15:2694. doi: 10.3390/pharmaceutics15122694. PubMed DOI PMC

Gaviraghi M., Tunici P., Valensin S., Rossi M., Giordano C., Magnoni L., Dandrea M., Montagna L., Ritelli R., Scarpa A., et al. Pancreatic cancer spheres are more than just aggregates of stem marker-positive cells. Biosci. Rep. 2011;31:45–55. doi: 10.1042/BSR20100018. PubMed DOI PMC

Nishino H., Takano S., Yoshitomi H., Suzuki K., Kagawa S., Shimazaki R., Shimizu H., Furukawa K., Miyazaki M., Ohtsuka M. Grainyhead-like 2 (GRHL2) regulates epithelial plasticity in pancreatic cancer progression. Cancer Med. 2017;6:2686–2696. doi: 10.1002/cam4.1212. PubMed DOI PMC

Anthiya S., Ozturk S.C., Yanik H., Tavukcuoglu E., Sahin A., Datta D., Charisse K., Alvarez D.M., Loza M.I., Calvo A., et al. Targeted siRNA lipid nanoparticles for the treatment of KRAS-mutant tumors. J. Control. Release. 2023;357:67–83. doi: 10.1016/j.jconrel.2023.03.016. PubMed DOI

Xu D., Yuan H., Meng Z., Yang C., Li Z., Li M., Zhang Z., Gan Y., Tu H. Cadherin 13 Inhibits Pancreatic Cancer Progression and Epithelial-mesenchymal Transition by Wnt/beta-Catenin Signaling. J. Cancer. 2020;11:2101–2112. doi: 10.7150/jca.37762. PubMed DOI PMC

Nguyen H.D., Lin C.C. Viscoelastic stiffening of gelatin hydrogels for dynamic culture of pancreatic cancer spheroids. Acta Biomater. 2024;177:203–215. doi: 10.1016/j.actbio.2024.02.010. PubMed DOI PMC

Kettler B., Trauzold A., Roder C., Egberts J.H., Kalthoff H. Topology impacts TRAIL therapy: Differences in primary cancer growth and liver metastasis between orthotopic and subcutaneous xenotransplants of pancreatic ductal adenocarcinoma cells. Hepatobiliary Pancreat. Dis. Int. 2021;20:279–284. doi: 10.1016/j.hbpd.2021.04.005. PubMed DOI

Feng H., Ou B.C., Zhao J.K., Yin S., Lu A.G., Oechsle E., Thasler W.E. Homogeneous pancreatic cancer spheroids mimic growth pattern of circulating tumor cell clusters and macrometastases: Displaying heterogeneity and crater-like structure on inner layer. J. Cancer Res. Clin. Oncol. 2017;143:1771–1786. doi: 10.1007/s00432-017-2434-2. PubMed DOI PMC

Fiore P.F., Di Pace A.L., Conti L.A., Tumino N., Besi F., Scaglione S., Munari E., Moretta L., Vacca P. Different effects of NK cells and NK-derived soluble factors on cell lines derived from primary or metastatic pancreatic cancers. Cancer Immunol. Immunother. 2023;72:1417–1428. doi: 10.1007/s00262-022-03340-z. PubMed DOI PMC

Curley R.C., Burke C.S., Gkika K.S., Noorani S., Walsh N., Keyes T.E. Phototoxicity of Tridentate Ru(II) Polypyridyl Complex with Expanded Bite Angles toward Mammalian Cells and Multicellular Tumor Spheroids. Inorg. Chem. 2023;62:13089–13102. doi: 10.1021/acs.inorgchem.3c01982. PubMed DOI PMC

Gagliano N., Celesti G., Tacchini L., Pluchino S., Sforza C., Rasile M., Valerio V., Laghi L., Conte V., Procacci P. Epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma: Characterization in a 3D-cell culture model. World J. Gastroenterol. 2016;22:4466–4483. doi: 10.3748/wjg.v22.i18.4466. PubMed DOI PMC

Gang J., Park S.B., Hyung W., Choi E.H., Wen J., Kim H.S., Shul Y.G., Haam S., Song S.Y. Magnetic poly epsilon-caprolactone nanoparticles containing Fe3O4 and gemcitabine enhance anti-tumor effect in pancreatic cancer xenograft mouse model. J. Drug Target. 2007;15:445–453. doi: 10.1080/10611860701453901. PubMed DOI

Mohammad R.M., Al-Katib A., Pettit G.R., Vaitkevicius V.K., Joshi U., Adsay V., Majumdar A.P., Sarkar F.H. An orthotopic model of human pancreatic cancer in severe combined immunodeficient mice: Potential application for preclinical studies. Clin. Cancer Res. 1998;4:887–894. PubMed

Usha L., Klapko O., Edassery S. Xenogeneic fibroblasts inhibit the growth of the breast and ovarian cancer cell lines in co-culture. Neoplasma. 2021;68:1265–1271. doi: 10.4149/neo_2021_210226N252. PubMed DOI

Chen S.T., Kuo T.C., Liao Y.Y., Lin M.C., Tien Y.W., Huang M.C. Silencing of MUC20 suppresses the malignant character of pancreatic ductal adenocarcinoma cells through inhibition of the HGF/MET pathway. Oncogene. 2018;37:6041–6053. doi: 10.1038/s41388-018-0403-0. PubMed DOI PMC

Lal S., Cheung E.C., Zarei M., Preet R., Chand S.N., Mambelli-Lisboa N.C., Romeo C., Stout M.C., Londin E., Goetz A., et al. CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype. Mol. Cancer Res. 2017;15:696–707. doi: 10.1158/1541-7786.MCR-16-0361. PubMed DOI PMC

Fredebohm J., Boettcher M., Eisen C., Gaida M.M., Heller A., Keleg S., Tost J., Greulich-Bode K.M., Hotz-Wagenblatt A., Lathrop M., et al. Establishment and characterization of a highly tumourigenic and cancer stem cell enriched pancreatic cancer cell line as a well defined model system. PLoS ONE. 2012;7:e48503. doi: 10.1371/journal.pone.0048503. PubMed DOI PMC

Mohammad R.M., Dugan M.C., Mohamed A.N., Almatchy V.P., Flake T.M., Dergham S.T., Shields A.F., Al-Katib A.A., Vaitkevicius V.K., Sarkar F.H. Establishment of a human pancreatic tumor xenograft model: Potential application for preclinical evaluation of novel therapeutic agents. Pancreas. 1998;16:19–25. doi: 10.1097/00006676-199801000-00004. PubMed DOI

Matsuda Y., Ishiwata T., Kawamoto Y., Kawahara K., Peng W.X., Yamamoto T., Naito Z. Morphological and cytoskeletal changes of pancreatic cancer cells in three-dimensional spheroidal culture. Med. Mol. Morphol. 2010;43:211–217. doi: 10.1007/s00795-010-0497-0. PubMed DOI

Murota Y., Nagane M., Wu M., Santra M., Venkateswaran S., Tanaka S., Bradley M., Taga T., Tabu K. A niche-mimicking polymer hydrogel-based approach to identify molecular targets for tackling human pancreatic cancer stem cells. Inflamm. Regen. 2023;43:46. doi: 10.1186/s41232-023-00296-0. PubMed DOI PMC

Hollevoet K., Mason-Osann E., Liu X.F., Imhof-Jung S., Niederfellner G., Pastan I. In vitro and in vivo activity of the low-immunogenic antimesothelin immunotoxin RG7787 in pancreatic cancer. Mol. Cancer Ther. 2014;13:2040–2049. doi: 10.1158/1535-7163.MCT-14-0089-T. PubMed DOI PMC

Tomar S., Zhang J., Khanal M., Hong J., Venugopalan A., Jiang Q., Sengupta M., Miettinen M., Li N., Pastan I., et al. Development of Highly Effective Anti-Mesothelin hYP218 Chimeric Antigen Receptor T Cells with Increased Tumor Infiltration and Persistence for Treating Solid Tumors. Mol. Cancer Ther. 2022;21:1195–1206. doi: 10.1158/1535-7163.MCT-22-0073. PubMed DOI PMC

Ikeda Y., Ezaki M., Hayashi I., Yasuda D., Nakayama K., Kono A. Establishment and characterization of human pancreatic cancer cell lines in tissue culture and in nude mice. Jpn. J. Cancer Res. 1990;81:987–993. doi: 10.1111/j.1349-7006.1990.tb03336.x. PubMed DOI PMC

Shichi Y., Gomi F., Hasegawa Y., Nonaka K., Shinji S., Takahashi K., Ishiwata T. Artificial intelligence-based analysis of time-lapse images of sphere formation and process of plate adhesion and spread of pancreatic cancer cells. Front. Cell Dev. Biol. 2023;11:1290753. doi: 10.3389/fcell.2023.1290753. PubMed DOI PMC

Xiong W., Friese-Hamim M., Johne A., Stroh C., Klevesath M., Falchook G.S., Hong D.S., Girard P., El Bawab S. Translational pharmacokinetic-pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose. CPT Pharmacomet. Syst. Pharmacol. 2021;10:428–440. doi: 10.1002/psp4.12602. PubMed DOI PMC

Ghosh S., Lovell J.F. Two Laser Treatments Can Improve Tumor Ablation Efficiency of Chemophototherapy. Pharmaceutics. 2021;13:2183. doi: 10.3390/pharmaceutics13122183. PubMed DOI PMC

Heike M., Rohrig O., Gabbert H.E., Moll R., Meyer zum Buschenfelde K.H., Dippold W.G., Knuth A. New cell lines of gastric and pancreatic cancer: Distinct morphology, growth characteristics, expression of epithelial and immunoregulatory antigens. Virchows Arch. 1995;426:375–384. doi: 10.1007/BF00191347. PubMed DOI

Hlavaty J., Petznek H., Holzmuller H., Url A., Jandl G., Berger A., Salmons B., Gunzburg W.H., Renner M. Evaluation of a gene-directed enzyme-product therapy (GDEPT) in human pancreatic tumor cells and their use as in vivo models for pancreatic cancer. PLoS ONE. 2012;7:e40611. doi: 10.1371/journal.pone.0040611. PubMed DOI PMC

Kalinina T., Gungor C., Thieltges S., Moller-Krull M., Penas E.M., Wicklein D., Streichert T., Schumacher U., Kalinin V., Simon R., et al. Establishment and characterization of a new human pancreatic adenocarcinoma cell line with high metastatic potential to the lung. BMC Cancer. 2010;10:295. doi: 10.1186/1471-2407-10-295. PubMed DOI PMC

Yanagihara K., Kubo T., Mihara K., Kuwata T., Ochiai A., Seyama T., Yokozaki H. Development and Biological Analysis of a Novel Orthotopic Peritoneal Dissemination Mouse Model Generated Using a Pancreatic Ductal Adenocarcinoma Cell Line. Pancreas. 2019;48:315–322. doi: 10.1097/MPA.0000000000001253. PubMed DOI PMC

Blackham A.U., Northrup S.A., Willingham M., Sirintrapun J., Russell G.B., Lyles D.S., Stewart J.H. Molecular determinants of susceptibility to oncolytic vesicular stomatitis virus in pancreatic adenocarcinoma. J. Surg. Res. 2014;187:412–426. doi: 10.1016/j.jss.2013.10.032. PubMed DOI PMC

Man Y.K.S., Davies J.A., Coughlan L., Pantelidou C., Blazquez-Moreno A., Marshall J.F., Parker A.L., Hallden G. The Novel Oncolytic Adenoviral Mutant Ad5-3Delta-A20T Retargeted to alphavbeta6 Integrins Efficiently Eliminates Pancreatic Cancer Cells. Mol. Cancer Ther. 2018;17:575–587. doi: 10.1158/1535-7163.MCT-17-0671. PubMed DOI

Xu Y., Fu J., Henderson M., Lee F., Jurcak N., Henn A., Wahl J., Shao Y., Wang J., Lyman M., et al. CLDN18.2 BiTE Engages Effector and Regulatory T Cells for Antitumor Immune Response in Preclinical Models of Pancreatic Cancer. Gastroenterology. 2023;165:1219–1232. doi: 10.1053/j.gastro.2023.06.037. PubMed DOI PMC

Salem A.F., Bonuccelli G., Bevilacqua G., Arafat H., Pestell R.G., Sotgia F., Lisanti M.P. Caveolin-1 promotes pancreatic cancer cell differentiation and restores membranous E-cadherin via suppression of the epithelial-mesenchymal transition. Cell Cycle. 2011;10:3692–3700. doi: 10.4161/cc.10.21.17895. PubMed DOI PMC

Kaye E.G., Kailass K., Sadovski O., Beharry A.A. A Green-Absorbing, Red-Fluorescent Phenalenone-Based Photosensitizer as a Theranostic Agent for Photodynamic Therapy. ACS Med. Chem. Lett. 2021;12:1295–1301. doi: 10.1021/acsmedchemlett.1c00284. PubMed DOI PMC

Shen Y.J., Cao J., Sun F., Cai X.L., Li M.M., Zheng N.N., Qu C.Y., Zhang Y., Shen F., Zhou M., et al. Effect of photodynamic therapy with (17R,18R)-2-(1-hexyloxyethyl)-2-devinyl chlorine E6 trisodium salt on pancreatic cancer cells in vitro and in vivo. World J. Gastroenterol. 2018;24:5246–5258. doi: 10.3748/wjg.v24.i46.5246. PubMed DOI PMC

Alves F., Contag S., Missbach M., Kaspareit J., Nebendahl K., Borchers U., Heidrich B., Streich R., Hiddemann W. An orthotopic model of ductal adenocarcinoma of the pancreas in severe combined immunodeficient mice representing all steps of the metastatic cascade. Pancreas. 2001;23:227–235. doi: 10.1097/00006676-200110000-00002. PubMed DOI

Vankova K., Markova I., Jasprova J., Dvorak A., Subhanova I., Zelenka J., Novosadova I., Rasl J., Vomastek T., Sobotka R., et al. Chlorophyll-Mediated Changes in the Redox Status of Pancreatic Cancer Cells Are Associated with Its Anticancer Effects. Oxid. Med. Cell. Longev. 2018;2018:4069167. doi: 10.1155/2018/4069167. PubMed DOI PMC

Zhao X., Li D.C., Zhu X.G., Gan W.J., Li Z., Xiong F., Zhang Z.X., Zhang G.B., Zhang X.G., Zhao H. B7-H3 overexpression in pancreatic cancer promotes tumor progression. Int. J. Mol. Med. 2013;31:283–291. doi: 10.3892/ijmm.2012.1212. PubMed DOI PMC

Chen J., Liu T.H., Guo X.Y., Ye S.F. Two new human exocrine pancreatic adenocarcinoma cell lines in vitro and in vivo. Chin. Med. J. 1990;103:369–375. PubMed

Wei H.J., Yin T., Zhu Z., Shi P.F., Tian Y., Wang C.Y. Expression of CD44, CD24 and ESA in pancreatic adenocarcinoma cell lines varies with local microenvironment. Hepatobiliary Pancreat. Dis. Int. 2011;10:428–434. doi: 10.1016/S1499-3872(11)60073-8. PubMed DOI

Kumar M., Liu Z.R., Thapa L., Wang D.Y., Tian R., Qin R.Y. Mechanisms of inhibition of growth of human pancreatic carcinoma implanted in nude mice by somatostatin receptor subtype 2. Pancreas. 2004;29:141–151. doi: 10.1097/00006676-200408000-00009. PubMed DOI

Zhu H., Liang Z.Y., Ren X.Y., Liu T.H. Small interfering RNAs targeting mutant K-ras inhibit human pancreatic carcinoma cells growth in vitro and in vivo. Cancer Biol. Ther. 2006;5:1693–1698. doi: 10.4161/cbt.5.12.3466. PubMed DOI

Yano T., Ishikura H., Kato H., Ogawa Y., Kondo S., Kato H., Yoshiki T. Vaccination effect of interleukin-6-producing pancreatic cancer cells in nude mice: A model of tumor prevention and treatment in immune-compromised patients. Jpn. J. Cancer Res. 2001;92:83–87. doi: 10.1111/j.1349-7006.2001.tb01051.x. PubMed DOI PMC

Shichinohe T., Senmaru N., Furuuchi K., Ogiso Y., Ishikura H., Yoshiki T., Takahashi T., Kato H., Kuzumaki N. Suppression of pancreatic cancer by the dominant negative ras mutant, N116Y. J. Surg. Res. 1996;66:125–130. doi: 10.1006/jsre.1996.0383. PubMed DOI

Du X., He K., Huang Y., Xu Z., Kong M., Zhang J., Cao J., Teng L. Establishment of a novel human cell line retaining the characteristics of the original pancreatic adenocarcinoma, and evaluation of MEK as a therapeutic target. Int. J. Oncol. 2020;56:761–771. doi: 10.3892/ijo.2020.4965. PubMed DOI PMC

Rahman A., Matsuyama M., Ebihara A., Shibayama Y., Hasan A.U., Nakagami H., Suzuki F., Sun J., Kobayashi T., Hayashi H., et al. Antiproliferative Effects of Monoclonal Antibodies against (Pro)Renin Receptor in Pancreatic Ductal Adenocarcinoma. Mol. Cancer Ther. 2020;19:1844–1855. doi: 10.1158/1535-7163.MCT-19-0228. PubMed DOI

Shichi Y., Gomi F., Ueda Y., Nonaka K., Hasegawa F., Hasegawa Y., Hinata N., Yoshimura H., Yamamoto M., Takahashi K., et al. Multiple cystic sphere formation from PK-8 cells in three-dimensional culture. Biochem. Biophys. Rep. 2022;32:101339. doi: 10.1016/j.bbrep.2022.101339. PubMed DOI PMC

Hoshida T., Sunamura M., Duda D.G., Egawa S., Miyazaki S., Shineha R., Hamada H., Ohtani H., Satomi S., Matsuno S. Gene therapy for pancreatic cancer using an adenovirus vector encoding soluble flt-1 vascular endothelial growth factor receptor. Pancreas. 2002;25:111–121. doi: 10.1097/00006676-200208000-00001. PubMed DOI

Suemizu H., Monnai M., Ohnishi Y., Ito M., Tamaoki N., Nakamura M. Identification of a key molecular regulator of liver metastasis in human pancreatic carcinoma using a novel quantitative model of metastasis in NOD/SCID/gammacnull (NOG) mice. Int. J. Oncol. 2007;31:741–751. doi: 10.3892/ijo.31.4.741. PubMed DOI

Hafeez B.B., Mustafa A., Fischer J.W., Singh A., Zhong W., Shekhani M.O., Meske L., Havighurst T., Kim K., Verma A.K. alpha-Mangostin: A dietary antioxidant derived from the pericarp of Garcinia mangostana L. inhibits pancreatic tumor growth in xenograft mouse model. Antioxid. Redox Signal. 2014;21:682–699. doi: 10.1089/ars.2013.5212. PubMed DOI PMC

Cykowiak M., Kleszcz R., Kucinska M., Paluszczak J., Szaefer H., Plewinski A., Piotrowska-Kempisty H., Murias M., Krajka-Kuzniak V. Attenuation of Pancreatic Cancer In Vitro and In Vivo via Modulation of Nrf2 and NF-kappaB Signaling Pathways by Natural Compounds. Cells. 2021;10:3556. doi: 10.3390/cells10123556. PubMed DOI PMC

Brancato V., Comunanza V., Imparato G., Cora D., Urciuolo F., Noghero A., Bussolino F., Netti P.A. Bioengineered tumoral microtissues recapitulate desmoplastic reaction of pancreatic cancer. Acta Biomater. 2017;49:152–166. doi: 10.1016/j.actbio.2016.11.072. PubMed DOI

Cherubini G., Kallin C., Mozetic A., Hammaren-Busch K., Muller H., Lemoine N.R., Hallden G. The oncolytic adenovirus AdDeltaDelta enhances selective cancer cell killing in combination with DNA-damaging drugs in pancreatic cancer models. Gene Ther. 2011;18:1157–1165. doi: 10.1038/gt.2011.141. PubMed DOI

Dandawate P., Ghosh C., Palaniyandi K., Paul S., Rawal S., Pradhan R., Sayed A.A.A., Choudhury S., Standing D., Subramaniam D., et al. The Histone Demethylase KDM3A, Increased in Human Pancreatic Tumors, Regulates Expression of DCLK1 and Promotes Tumorigenesis in Mice. Gastroenterology. 2019;157:1646–1659.e1611. doi: 10.1053/j.gastro.2019.08.018. PubMed DOI PMC

Lachowski D., Matellan C., Cortes E., Saiani A., Miller A.F., Del Rio Hernandez A.E. Self-Assembling Polypeptide Hydrogels as a Platform to Recapitulate the Tumor Microenvironment. Cancers. 2021;13:3286. doi: 10.3390/cancers13133286. PubMed DOI PMC

Taniguchi S., Iwamura T., Katsuki T. Correlation between spontaneous metastatic potential and type I collagenolytic activity in a human pancreatic cancer cell line (SUIT-2) and sublines. Clin. Exp. Metastasis. 1992;10:259–266. doi: 10.1007/BF00133561. PubMed DOI

Hennig R., Ventura J., Segersvard R., Ward E., Ding X.Z., Rao S.M., Jovanovic B.D., Iwamura T., Talamonti M.S., Bell R.H., Jr., et al. LY293111 improves efficacy of gemcitabine therapy on pancreatic cancer in a fluorescent orthotopic model in athymic mice. Neoplasia. 2005;7:417–425. doi: 10.1593/neo.04559. PubMed DOI PMC

Kramer B., Haan L., Vermeer M., Olivier T., Hankemeier T., Vulto P., Joore J., Lanz H.L. Interstitial Flow Recapitulates Gemcitabine Chemoresistance in A 3D Microfluidic Pancreatic Ductal Adenocarcinoma Model by Induction of Multidrug Resistance Proteins. Int. J. Mol. Sci. 2019;20:4647. doi: 10.3390/ijms20184647. PubMed DOI PMC

Kurahara H., Bohl C., Natsugoe S., Nishizono Y., Harihar S., Sharma R., Iwakuma T., Welch D.R. Suppression of pancreatic cancer growth and metastasis by HMP19 identified through genome-wide shRNA screen. Int. J. Cancer. 2016;139:628–638. doi: 10.1002/ijc.30110. PubMed DOI PMC

Ye J., Kawaguchi M., Haruyama Y., Kanemaru A., Fukushima T., Yamamoto K., Lin C.Y., Kataoka H. Loss of hepatocyte growth factor activator inhibitor type 1 participates in metastatic spreading of human pancreatic cancer cells in a mouse orthotopic transplantation model. Cancer Sci. 2014;105:44–51. doi: 10.1111/cas.12306. PubMed DOI PMC

Diaz V.M., Planaguma J., Thomson T.M., Reventos J., Paciucci R. Tissue plasminogen activator is required for the growth, invasion, and angiogenesis of pancreatic tumor cells. Gastroenterology. 2002;122:806–819. doi: 10.1053/gast.2002.31885. PubMed DOI

Liu C., Deng S., Jin K., Gong Y., Cheng H., Fan Z., Qian Y., Huang Q., Ni Q., Luo G., et al. Lewis antigen-negative pancreatic cancer: An aggressive subgroup. Int. J. Oncol. 2020;56:900–908. doi: 10.3892/ijo.2020.4989. PubMed DOI PMC

Yanagihara K., Takigahira M., Tanaka H., Arao T., Aoyagi Y., Oda T., Ochiai A., Nishio K. Establishment and molecular profiling of a novel human pancreatic cancer panel for 5-FU. Cancer Sci. 2008;99:1859–1864. doi: 10.1111/j.1349-7006.2008.00896.x. PubMed DOI PMC

Kozono S., Ohuchida K., Eguchi D., Ikenaga N., Fujiwara K., Cui L., Mizumoto K., Tanaka M. Pirfenidone inhibits pancreatic cancer desmoplasia by regulating stellate cells. Cancer Res. 2013;73:2345–2356. doi: 10.1158/0008-5472.CAN-12-3180. PubMed DOI

Kawano K., Iwamura T., Yamanari H., Seo Y., Suganuma T., Chijiiwa K. Establishment and characterization of a novel human pancreatic cancer cell line (SUIT-4) metastasizing to lymph nodes and lungs in nude mice. Oncology. 2004;66:458–467. doi: 10.1159/000079500. PubMed DOI

Takahashi N., Aoyama F., Sawaguchi A. Three-dimensional culture of a pancreatic cancer cell line, SUIT-58, with air exposure can reflect the intrinsic features of the original tumor through electron microscopy. Microscopy. 2021;70:192–200. doi: 10.1093/jmicro/dfaa046. PubMed DOI

Sang M., Nakamura M., Ogata T., Sun D., Shimozato O., Nikaido T., Ozaki T. Impact of RUNX2 gene silencing on the gemcitabine sensitivity of p53-mutated pancreatic cancer MiaPaCa-2 spheres. Oncol. Rep. 2018;39:2749–2758. doi: 10.3892/or.2018.6344. PubMed DOI

Li M.M., Cao J., Yang J.C., Shen Y.J., Cai X.L., Chen Y.W., Qu C.Y., Zhang Y., Shen F., Xu L.M. Effects of arginine-glycine-aspartic acid peptide-conjugated quantum dots-induced photodynamic therapy on pancreatic carcinoma in vivo. Int. J. Nanomed. 2017;12:2769–2779. doi: 10.2147/IJN.S130799. PubMed DOI PMC

Weber H.L., Gidekel M., Werbajh S., Salvatierra E., Rotondaro C., Sganga L., Haab G.A., Curiel D.T., Cafferata E.G., Podhajcer O.L. A Novel CDC25B Promoter-Based Oncolytic Adenovirus Inhibited Growth of Orthotopic Human Pancreatic Tumors in Different Preclinical Models. Clin. Cancer Res. 2015;21:1665–1674. doi: 10.1158/1078-0432.CCR-14-2316. PubMed DOI

Okabe T., Yamaguchi N., Ohsawa N. Establishment and characterization of a carcinoembryonic antigen (CEA)-producing cell line from a human carcinoma of the exocrine pancreas. Cancer. 1983;51:662–668. doi: 10.1002/1097-0142(19830215)51:4<662::AID-CNCR2820510419>3.0.CO;2-X. PubMed DOI

Saxena S., Purohit A., Varney M.L., Hayashi Y., Singh R.K. Semaphorin-5A maintains epithelial phenotype of malignant pancreatic cancer cells. BMC Cancer. 2018;18:1283. doi: 10.1186/s12885-018-5204-x. PubMed DOI PMC

Stefano E., Cossa L.G., De Castro F., De Luca E., Vergaro V., My G., Rovito G., Migoni D., Muscella A., Marsigliante S., et al. Evaluation of the Antitumor Effects of Platinum-Based [Pt(η1-C2H4-OR)(DMSO)(phen)]+ (R = Me, Et) Cationic Organometallic Complexes on Chemoresistant Pancreatic Cancer Cell Lines. Bioinorg. Chem. Appl. 2023;2023:5564624. doi: 10.1155/2023/5564624. PubMed DOI PMC

Neureiter D., Zopf S., Dimmler A., Stintzing S., Hahn E.G., Kirchner T., Herold C., Ocker M. Different capabilities of morphological pattern formation and its association with the expression of differentiation markers in a xenograft model of human pancreatic cancer cell lines. Pancreatology. 2005;5:387–397. doi: 10.1159/000086539. PubMed DOI

Heger M. Editor’s inaugural issue foreword: Perspectives on translational and clinical research. J. Clin. Transl. Res. 2015;1:1–5. doi: 10.18053/jctres.201501.005. PubMed DOI PMC

Gioeli D., Snow C.J., Simmers M.B., Hoang S.A., Figler R.A., Allende J.A., Roller D.G., Parsons J.T., Wulfkuhle J.D., Petricoin E.F., et al. Development of a multicellular pancreatic tumor microenvironment system using patient-derived tumor cells. Lab Chip. 2019;19:1193–1204. doi: 10.1039/C8LC00755A. PubMed DOI PMC

Stokes J.B., Adair S.J., Slack-Davis J.K., Walters D.M., Tilghman R.W., Hershey E.D., Lowrey B., Thomas K.S., Bouton A.H., Hwang R.F., et al. Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Mol. Cancer Ther. 2011;10:2135–2145. doi: 10.1158/1535-7163.MCT-11-0261. PubMed DOI PMC

Walters D.M., Stokes J.B., Adair S.J., Stelow E.B., Borgman C.A., Lowrey B.T., Xin W., Blais E.M., Lee J.K., Papin J.A., et al. Clinical, molecular and genetic validation of a murine orthotopic xenograft model of pancreatic adenocarcinoma using fresh human specimens. PLoS ONE. 2013;8:e77065. doi: 10.1371/journal.pone.0077065. PubMed DOI PMC

Gorg C., Seifart U., Gorg K., Zugmaier G. Color Doppler sonographic mapping of pulmonary lesions: Evidence of dual arterial supply by spectral analysis. J. Ultrasound Med. 2003;22:1033–1039. doi: 10.7863/jum.2003.22.10.1033. PubMed DOI

Baronzio G., Schwartz L., Kiselevsky M., Guais A., Sanders E., Milanesi G., Baronzio M., Freitas I. Tumor interstitial fluid as modulator of cancer inflammation, thrombosis, immunity and angiogenesis. Anticancer Res. 2012;32:405–414. PubMed

Majumder S., Islam M.T., Righetti R. Non-invasive imaging of interstitial fluid transport parameters in solid tumors in vivo. Sci. Rep. 2023;13:7132. doi: 10.1038/s41598-023-33651-9. PubMed DOI PMC

Di Maggio F., Arumugam P., Delvecchio F.R., Batista S., Lechertier T., Hodivala-Dilke K., Kocher H.M. Pancreatic stellate cells regulate blood vessel density in the stroma of pancreatic ductal adenocarcinoma. Pancreatology. 2016;16:995–1004. doi: 10.1016/j.pan.2016.05.393. PubMed DOI PMC

Korbelik M. Induction of tumor immunity by photodynamic therapy. J. Clin. Laser Med. Surg. 1996;14:329–334. doi: 10.1089/clm.1996.14.329. PubMed DOI

van Duijnhoven F.H., Aalbers R.I., Rovers J.P., Terpstra O.T., Kuppen P.J. The immunological consequences of photodynamic treatment of cancer, a literature review. Immunobiology. 2003;207:105–113. doi: 10.1078/0171-2985-00221. PubMed DOI

Canti G., De Simone A., Korbelik M. Photodynamic therapy and the immune system in experimental oncology. Photochem. Photobiol. Sci. 2002;1:79–80. doi: 10.1039/b109007k. PubMed DOI

Castano A.P., Mroz P., Hamblin M.R. Photodynamic therapy and anti-tumour immunity. Nat. Rev. Cancer. 2006;6:535–545. doi: 10.1038/nrc1894. PubMed DOI PMC

Kousis P.C., Henderson B.W., Maier P.G., Gollnick S.O. Photodynamic therapy enhancement of antitumor immunity is regulated by neutrophils. Cancer Res. 2007;67:10501–10510. doi: 10.1158/0008-5472.CAN-07-1778. PubMed DOI PMC

Gollnick S.O., Evans S.S., Baumann H., Owczarczak B., Maier P., Vaughan L., Wang W.C., Unger E., Henderson B.W. Role of cytokines in photodynamic therapy-induced local and systemic inflammation. Br. J. Cancer. 2003;88:1772–1779. doi: 10.1038/sj.bjc.6600864. PubMed DOI PMC

Hwang H.S., Shin H., Han J., Na K. Combination of photodynamic therapy (PDT) and anti-tumor immunity in cancer therapy. J. Pharm. Investig. 2018;48:143–151. doi: 10.1007/s40005-017-0377-x. PubMed DOI PMC

Korbelik M., Krosl G., Krosl J., Dougherty G.J. The role of host lymphoid populations in the response of mouse EMT6 tumor to photodynamic therapy. Cancer Res. 1996;56:5647–5652. PubMed

Korbelik M., Dougherty G.J. Photodynamic therapy-mediated immune response against subcutaneous mouse tumors. Cancer Res. 1999;59:1941–1946. PubMed

Hendrzak-Henion J.A., Knisely T.L., Cincotta L., Cincotta E., Cincotta A.H. Role of the immune system in mediating the antitumor effect of benzophenothiazine photodynamic therapy. Photochem. Photobiol. 1999;69:575–581. doi: 10.1111/j.1751-1097.1999.tb03330.x. PubMed DOI

Castano A.P., Liu Q., Hamblin M.R. A green fluorescent protein-expressing murine tumour but not its wild-type counterpart is cured by photodynamic therapy. Br. J. Cancer. 2006;94:391–397. doi: 10.1038/sj.bjc.6602953. PubMed DOI PMC

Uenaka A., Nakayama E. Murine leukemia RL male 1 and sarcoma Meth A antigens recognized by cytotoxic T lymphocytes (CTL) Cancer Sci. 2003;94:931–936. doi: 10.1111/j.1349-7006.2003.tb01380.x. PubMed DOI PMC

Broekgaarden M., Kos M., Jurg F.A., van Beek A.A., van Gulik T.M., Heger M. Inhibition of NF-kappaB in Tumor Cells Exacerbates Immune Cell Activation Following Photodynamic Therapy. Int. J. Mol. Sci. 2015;16:19960–19977. doi: 10.3390/ijms160819960. PubMed DOI PMC

Chen J., Liao S., Xiao Z., Pan Q., Wang X., Shen K., Wang S., Yang L., Guo F., Liu H.F., et al. The development and improvement of immunodeficient mice and humanized immune system mouse models. Front. Immunol. 2022;13:1007579. doi: 10.3389/fimmu.2022.1007579. PubMed DOI PMC

Partecke I.L., Kaeding A., Sendler M., Albers N., Kuhn J.P., Speerforck S., Roese S., Seubert F., Diedrich S., Kuehn S., et al. In vivo imaging of pancreatic tumours and liver metastases using 7 Tesla MRI in a murine orthotopic pancreatic cancer model and a liver metastases model. BMC Cancer. 2011;11:40. doi: 10.1186/1471-2407-11-40. PubMed DOI PMC

Courtin A., Richards F.M., Bapiro T.E., Bramhall J.L., Neesse A., Cook N., Krippendorff B.F., Tuveson D.A., Jodrell D.I. Anti-tumour efficacy of capecitabine in a genetically engineered mouse model of pancreatic cancer. PLoS ONE. 2013;8:e67330. doi: 10.1371/journal.pone.0067330. PubMed DOI PMC

Blaauboer A., Van Koetsveld P.M., Mustafa D.A.M., Dumas J., Dogan F., Van Zwienen S., Van Eijck C.H.J., Hofland L.J. Immunomodulatory antitumor effect of interferon-beta combined with gemcitabine in pancreatic cancer. Int. J. Oncol. 2022;61:97. doi: 10.3892/ijo.2022.5387. PubMed DOI

Nasiri E., Student M., Roth K., Siti Utami N., Huber M., Buchholz M., Gress T.M., Bauer C. IL18 Receptor Signaling Inhibits Intratumoral CD8+ T-Cell Migration in a Murine Pancreatic Cancer Model. Cells. 2023;12:456. doi: 10.3390/cells12030456. PubMed DOI PMC

Czaplinska D., Ialchina R., Andersen H.B., Yao J., Stigliani A., Dannesboe J., Flinck M., Chen X., Mitrega J., Gnosa S.P., et al. Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness. Int. J. Cancer. 2023;152:1210–1225. doi: 10.1002/ijc.34367. PubMed DOI PMC

Fukushima H., Furusawa A., Kato T., Wakiyama H., Takao S., Okuyama S., Choyke P.L., Kobayashi H. Intratumoral IL15 Improves Efficacy of Near-Infrared Photoimmunotherapy. Mol. Cancer Ther. 2023;22:1215–1227. doi: 10.1158/1535-7163.MCT-23-0210. PubMed DOI PMC

Zhou F., Yang J., Zhang Y., Liu M., Lang M.L., Li M., Chen W.R. Local Phototherapy Synergizes with Immunoadjuvant for Treatment of Pancreatic Cancer through Induced Immunogenic Tumor Vaccine. Clin. Cancer Res. 2018;24:5335–5346. doi: 10.1158/1078-0432.CCR-18-1126. PubMed DOI PMC

Torres M.P., Rachagani S., Souchek J.J., Mallya K., Johansson S.L., Batra S.K. Novel pancreatic cancer cell lines derived from genetically engineered mouse models of spontaneous pancreatic adenocarcinoma: Applications in diagnosis and therapy. PLoS ONE. 2013;8:e80580. doi: 10.1371/journal.pone.0080580. PubMed DOI PMC

Benali N., Cordelier P., Calise D., Pages P., Rochaix P., Nagy A., Esteve J.P., Pour P.M., Schally A.V., Vaysse N., et al. Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238. Proc. Natl. Acad. Sci. USA. 2000;97:9180–9185. doi: 10.1073/pnas.130196697. PubMed DOI PMC

Hirota M., Egami H., Mogaki M., Kazakoff K., Chaney W.G., Pour P.M. Relationship between blood group-A antigen expression and malignant potential in hamster pancreatic cancers. Teratog. Carcinog. Mutagen. 1993;13:217–224. doi: 10.1002/tcm.1770130503. PubMed DOI

Chang B.K., Gutman R. Chemotherapy of pancreatic adenocarcinoma: Initial report on two transplantable models in the Syrian hamster. Cancer Res. 1982;42:2666–2670. PubMed

Baptista M.S., Cadet J., Di Mascio P., Ghogare A.A., Greer A., Hamblin M.R., Lorente C., Nunez S.C., Ribeiro M.S., Thomas A.H., et al. Type I and Type II Photosensitized Oxidation Reactions: Guidelines and Mechanistic Pathways. Photochem. Photobiol. 2017;93:912–919. doi: 10.1111/php.12716. PubMed DOI PMC

Sitnik T.M., Hampton J.A., Henderson B.W. Reduction of tumour oxygenation during and after photodynamic therapy in vivo: Effects of fluence rate. Br. J. Cancer. 1998;77:1386–1394. doi: 10.1038/bjc.1998.231. PubMed DOI PMC

Debefve E., Pegaz B., van den Bergh H., Wagnieres G., Lange N., Ballini J.P. Video monitoring of neovessel occlusion induced by photodynamic therapy with verteporfin (Visudyne), in the CAM model. Angiogenesis. 2008;11:235–243. doi: 10.1007/s10456-008-9106-4. PubMed DOI PMC

Castano A.P., Demidova T.N., Hamblin M.R. Mechanisms in photodynamic therapy: Part three-Photosensitizer pharmacokinetics, biodistribution, tumor localization and modes of tumor destruction. Photodiagnosis Photodyn. Ther. 2005;2:91–106. doi: 10.1016/S1572-1000(05)00060-8. PubMed DOI PMC

Kwiatkowski S., Knap B., Przystupski D., Saczko J., Kedzierska E., Knap-Czop K., Kotlinska J., Michel O., Kotowski K., Kulbacka J. Photodynamic therapy—Mechanisms, photosensitizers and combinations. Biomed. Pharmacother. 2018;106:1098–1107. doi: 10.1016/j.biopha.2018.07.049. PubMed DOI

Dias L.M., de Keijzer M.J., Ernst D., Sharifi F., de Klerk D.J., Kleijn T.G., Desclos E., Kochan J.A., de Haan L.R., Franchi L.P., et al. Metallated phthalocyanines and their hydrophilic derivatives for multi-targeted oncological photodynamic therapy. J. Photochem. Photobiol. B. 2022;234:112500. doi: 10.1016/j.jphotobiol.2022.112500. PubMed DOI

Xie Q., Li Z., Liu Y., Zhang D., Su M., Niitsu H., Lu Y., Coffey R.J., Bai M. Translocator protein-targeted photodynamic therapy for direct and abscopal immunogenic cell death in colorectal cancer. Acta Biomater. 2021;134:716–729. doi: 10.1016/j.actbio.2021.07.052. PubMed DOI PMC

Lou J., Aragaki M., Bernards N., Kinoshita T., Mo J., Motooka Y., Ishiwata T., Gregor A., Chee T., Chen Z., et al. Repeated porphyrin lipoprotein-based photodynamic therapy controls distant disease in mouse mesothelioma via the abscopal effect. Nanophotonics. 2021;10:3279–3294. doi: 10.1515/nanoph-2021-0241. PubMed DOI PMC

Osuna de la Pena D., Trabulo S.M.D., Collin E., Liu Y., Sharma S., Tatari M., Behrens D., Erkan M., Lawlor R.T., Scarpa A., et al. Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology. Nat. Commun. 2021;12:5623. doi: 10.1038/s41467-021-25921-9. PubMed DOI PMC

Godier C., Baka Z., Lamy L., Gribova V., Marchal P., Lavalle P., Gaffet E., Bezdetnaya L., Alem H. A 3D Bio-Printed-Based Model for Pancreatic Ductal Adenocarcinoma. Diseases. 2024;12:206. doi: 10.3390/diseases12090206. PubMed DOI PMC

Sun H., Wang Y., Sun M., Ke X., Li C., Jin B., Pang M., Wang Y., Jiang S., Du L., et al. Developing Patient-Derived 3D-Bioprinting models of pancreatic cancer. J. Adv. Res. 2024 doi: 10.1016/j.jare.2024.09.011. in press . PubMed DOI

Haque M.R., Wessel C.R., Leary D.D., Wang C., Bhushan A., Bishehsari F. Patient-derived pancreatic cancer-on-a-chip recapitulates the tumor microenvironment. Microsyst. Nanoeng. 2022;8:36. doi: 10.1038/s41378-022-00370-6. PubMed DOI PMC

Sgarminato V., Marasso S.L., Cocuzza M., Scordo G., Ballesio A., Ciardelli G., Tonda-Turo C. PDAC-on-chip for in vitro modeling of stromal and pancreatic cancer cell crosstalk. Biomater. Sci. 2022;11:208–224. doi: 10.1039/D2BM00881E. PubMed DOI

Goluba K., Parfejevs V., Rostoka E., Jekabsons K., Blake I., Neimane A., Ule A.A., Rimsa R., Vangravs R., Pcolkins A., et al. Personalized PDAC chip with functional endothelial barrier for tumour biomarker detection: A platform for precision medicine applications. Mater. Today Bio. 2024;29:101262. doi: 10.1016/j.mtbio.2024.101262. PubMed DOI PMC

Geyer M., Schreyer D., Gaul L.M., Pfeffer S., Pilarsky C., Queiroz K. A microfluidic-based PDAC organoid system reveals the impact of hypoxia in response to treatment. Cell Death Discov. 2023;9:20. doi: 10.1038/s41420-023-01334-z. PubMed DOI PMC

Kumano K., Nakahashi H., Louphrasitthiphol P., Kuroda Y., Miyazaki Y., Shimomura O., Hashimoto S., Akashi Y., Mathis B.J., Kim J., et al. Hypoxia at 3D organoid establishment selects essential subclones within heterogenous pancreatic cancer. Front. Cell Dev. Biol. 2024;12:1327772. doi: 10.3389/fcell.2024.1327772. PubMed DOI PMC

Abou Khouzam R., Lehn J.M., Mayr H., Clavien P.A., Wallace M.B., Ducreux M., Limani P., Chouaib S. Hypoxia, a Targetable Culprit to Counter Pancreatic Cancer Resistance to Therapy. Cancers. 2023;15:1235. doi: 10.3390/cancers15041235. PubMed DOI PMC

Broekgaarden M., Weijer R., van Wijk A.C., Cox R.C., Egmond M.R., Hoebe R., van Gulik T.M., Heger M. Photodynamic Therapy with Liposomal Zinc Phthalocyanine and Tirapazamine Increases Tumor Cell Death via DNA Damage. J. Biomed. Nanotechnol. 2017;13:204–220. doi: 10.1166/jbn.2017.2327. PubMed DOI

Cros J., Raffenne J., Couvelard A., Pote N. Tumor Heterogeneity in Pancreatic Adenocarcinoma. Pathobiology. 2018;85:64–71. doi: 10.1159/000477773. PubMed DOI

Palma A.M., Vudatha V., Peixoto M.L., Madan E. Tumor heterogeneity: An oncogenic driver of PDAC progression and therapy resistance under stress conditions. Adv. Cancer Res. 2023;159:203–249. doi: 10.1016/bs.acr.2023.02.005. PubMed DOI

Evan T., Wang V.M., Behrens A. The roles of intratumour heterogeneity in the biology and treatment of pancreatic ductal adenocarcinoma. Oncogene. 2022;41:4686–4695. doi: 10.1038/s41388-022-02448-x. PubMed DOI PMC

Roos E., Soer E.C., Klompmaker S., Meijer L.L., Besselink M.G., Giovannetti E., Heger M., Kazemier G., Klumpen H.J., Takkenberg R.B., et al. Crossing borders: A systematic review with quantitative analysis of genetic mutations of carcinomas of the biliary tract. Crit. Rev. Oncol. Hematol. 2019;140:8–16. doi: 10.1016/j.critrevonc.2019.05.011. PubMed DOI

Patel T. Cholangiocarcinoma—Controversies and challenges. Nat. Rev. Gastroenterol. Hepatol. 2011;8:189–200. doi: 10.1038/nrgastro.2011.20. PubMed DOI PMC

Banales J.M., Marin J.J.G., Lamarca A., Rodrigues P.M., Khan S.A., Roberts L.R., Cardinale V., Carpino G., Andersen J.B., Braconi C., et al. Cholangiocarcinoma 2020: The next horizon in mechanisms and management. Nat. Rev. Gastroenterol. Hepatol. 2020;17:557–588. doi: 10.1038/s41575-020-0310-z. PubMed DOI PMC

de Klerk D.J., de Keijzer M.J., Dias L.M., Heemskerk J., de Haan L.R., Kleijn T.G., Franchi L.P., Heger M., Photodynamic Therapy Study G. Strategies for Improving Photodynamic Therapy Through Pharmacological Modulation of the Immediate Early Stress Response. Methods Mol. Biol. 2022;2451:405–480. doi: 10.1007/978-1-0716-2099-1_20. PubMed DOI

Moss D.M., Siccardi M. Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling. Br. J. Pharmacol. 2014;171:3963–3979. doi: 10.1111/bph.12604. PubMed DOI PMC

Kadam R.S., Bourne D.W., Kompella U.B. Nano-advantage in enhanced drug delivery with biodegradable nanoparticles: Contribution of reduced clearance. Drug Metab. Dispos. 2012;40:1380–1388. doi: 10.1124/dmd.112.044925. PubMed DOI PMC

Zhang A., Meng K., Liu Y., Pan Y., Qu W., Chen D., Xie S. Absorption, distribution, metabolism, and excretion of nanocarriers in vivo and their influences. Adv. Colloid. Interface Sci. 2020;284:102261. doi: 10.1016/j.cis.2020.102261. PubMed DOI

Liu W., Zhu Y., Ye L., Zhu Y., Wang Y. Comparison of tumor angiogenesis in subcutaneous and orthotopic LNCaP mouse models using contrast-enhanced ultrasound imaging. Transl. Cancer Res. 2021;10:3268–3277. doi: 10.21037/tcr-21-372. PubMed DOI PMC

Guerin M.V., Finisguerra V., Van den Eynde B.J., Bercovici N., Trautmann A. Preclinical murine tumor models: A structural and functional perspective. Elife. 2020;9:e50740. doi: 10.7554/eLife.50740. PubMed DOI PMC

Fung A.S., Lee C., Yu M., Tannock I.F. The effect of chemotherapeutic agents on tumor vasculature in subcutaneous and orthotopic human tumor xenografts. BMC Cancer. 2015;15:112. doi: 10.1186/s12885-015-1091-6. PubMed DOI PMC

Li M., Bosman E.D.C., Smith O.M., Lintern N., de Klerk D.J., Sun H., Cheng S., Pan W., Storm G., Khaled Y.S., et al. Comparative analysis of whole cell-derived vesicular delivery systems for photodynamic therapy of extrahepatic cholangiocarcinoma. J. Photochem. Photobiol. B. 2024;254:112903. doi: 10.1016/j.jphotobiol.2024.112903. PubMed DOI

Price O.T., Lau C., Zucker R.M. Quantitative fluorescence of 5-FU-treated fetal rat limbs using confocal laser scanning microscopy and Lysotracker Red. Cytom. A. 2003;53:9–21. doi: 10.1002/cyto.a.10036. PubMed DOI

Zhitomirsky B., Farber H., Assaraf Y.G. LysoTracker and MitoTracker Red are transport substrates of P-glycoprotein: Implications for anticancer drug design evading multidrug resistance. J. Cell. Mol. Med. 2018;22:2131–2141. doi: 10.1111/jcmm.13485. PubMed DOI PMC

Heger M., Salles I.I., van Vuure W., Hamelers I.H., de Kroon A.I., Deckmyn H., Beek J.F. On the interaction of fluorophore-encapsulating PEGylated lecithin liposomes with hamster and human platelets. Microvasc. Res. 2009;78:57–66. doi: 10.1016/j.mvr.2009.02.006. PubMed DOI

Barton B.E., Karras J.G., Murphy T.F., Barton A., Huang H.F. Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: Direct STAT3 inhibition induces apoptosis in prostate cancer lines. Mol. Cancer Ther. 2004;3:11–20. doi: 10.1158/1535-7163.11.3.1. PubMed DOI

Reiniers M.J., de Haan L.R., Reeskamp L.F., Broekgaarden M., van Golen R.F., Heger M. Analysis and Optimization of Conditions for the Use of 2′,7′-Dichlorofluorescein Diacetate in Cultured Hepatocytes. Antioxidants. 2021;10:674. doi: 10.3390/antiox10050674. PubMed DOI PMC

Harada M., Woodhams J., MacRobert A.J., Feneley M.R., Kato H., Bown S.G. The vascular response to photodynamic therapy with ATX-S10Na(II) in the normal rat colon. J. Photochem. Photobiol. B. 2005;79:223–230. doi: 10.1016/j.jphotobiol.2004.08.011. PubMed DOI

Suzuki T., Tanaka M., Sasaki M., Ichikawa H., Nishie H., Kataoka H. Vascular Shutdown by Photodynamic Therapy Using Talaporfin Sodium. Cancers. 2020;12:2369. doi: 10.3390/cancers12092369. PubMed DOI PMC