Placental mesenchymal stem cells: A promising platform for advancing gene therapy in pancreatic ductal adenocarcinoma
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
40768934
DOI
10.1016/j.biopha.2025.118428
PII: S0753-3322(25)00622-5
Knihovny.cz E-zdroje
- Klíčová slova
- Conditioned medium, Extracellular vesicle, Gene-directed enzyme prodrug therapy, Mesenchymal stem cell, Pancreatic ductal adenocarcinoma,
- MeSH
- cytosindeaminasa genetika metabolismus MeSH
- duktální karcinom slinivky břišní * terapie genetika patologie MeSH
- flucytosin farmakologie metabolismus MeSH
- fluoruracil farmakologie metabolismus MeSH
- genetická terapie * metody MeSH
- kokultivační techniky MeSH
- kultivační média speciální MeSH
- lidé MeSH
- mezenchymální kmenové buňky * metabolismus MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory slinivky břišní * terapie genetika patologie MeSH
- pentosyltransferasy genetika metabolismus MeSH
- placenta * cytologie MeSH
- prekurzory léčiv MeSH
- těhotenství MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- cytosindeaminasa MeSH
- flucytosin MeSH
- fluoruracil MeSH
- kultivační média speciální MeSH
- pentosyltransferasy MeSH
- prekurzory léčiv MeSH
- uracil phosphoribosyltransferase MeSH Prohlížeč
The extreme lethality and limited treatment options for pancreatic ductal adenocarcinoma (PDAC) underscore the urgent need for innovative therapeutic strategies. This study presents the first preclinical investigation of a cell-free gene-directed enzyme prodrug therapy (GDEPT) based on conditioned medium (CM) from placenta-derived mesenchymal stem cells (PlacMSCs) engineered to express the yeast cytosine deaminase::uracil phosphoribosyltransferase (yCD::UPRT) fusion enzyme. The CM was concentrated tenfold (cCM) and characterized by proteomics, transmission electron microscopy, and Western blotting, confirming extracellular vesicle (EV) enrichment and UPRT expression. Therapeutic efficacy was evaluated in coculture models comprising PDAC cell lines (BxPC-3, MIA PaCa-2, SU.86.86), patient-derived xenograft organoids (PDXOs), and cancer-associated fibroblasts (PCAFs). Immunocytochemistry and Western blot analyses revealed a predominant myofibroblastic CAF phenotype, characterized by strong alpha-smooth muscle actin (αSMA) expression and low interleukin-6 levels. Treatment with yCD::UPRT-PlacMSC-cCM in the presence of 5-fluorocytosine (5-FC) enabled efficient enzymatic conversion to 5-fluorouracil (5-FU), yielding 10 μg/mL from an initial 100 μg/mL of 5-FC. This resulted in robust, dose-dependent cytotoxicity (50 % to 80 % reduction in viability) across monocultures and stromal-rich cocultures, effectively overcoming PCAF-mediated drug resistance. Therapeutic response was governed primarily by tumor cell characteristics rather than PCAF heterogeneity. In PDXOs derived from two early-stage (IA, IIB) primary tumors and one metastatic lesion, 100 µL of yCD::UPRT-PlacMSC-cCM induced cytotoxicity comparable to 1 μg/mL of 5-FU, while 25 µL was insufficient to significantly reduce viability. Collectively, these findings demonstrate that yCD::UPRT-PlacMSC-cCM delivers potent, stromal-bypassing cytotoxicity in PDAC models and represents a promising cell-free therapeutic approach for this treatment-refractory cancer.
Cancer Research Institute Biomedical Research Center Slovak Academy of Sciences Bratislava Slovakia
Central European Institute of Technology Masaryk University Brno Czech Republic
Department of Pathology National Cancer Institute in Bratislava Bratislava Slovakia
Department of Stem Cell Preparation St Elisabeth Cancer Institute Bratislava Slovakia
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