Melanoma phenotype plasticity underlies tumour dissemination and resistance to therapy, yet its regulation is incompletely understood. In vivo switching between a more differentiated, proliferative phenotype and a dedifferentiated, invasive phenotype is directed by the tumour microenvironment. We found that treatment of partially dedifferentiated, invasive A375M2 cells with two structurally unrelated p38 MAPK inhibitors, SB2021920 and BIRB796, induces a phenotype switch in 3D collagen, as documented by increased expression of melanocyte differentiation markers and a loss of invasive phenotype markers. The phenotype is accompanied by morphological change corresponding to amoeboid-mesenchymal transition. We performed RNA sequencing with an Illumina HiSeq platform to fully characterise transcriptome changes underlying the switch. Gene expression results obtained with RNA-seq were validated by comparing them with RT-qPCR. Transcriptomic data generated in the study will extend the present understanding of phenotype plasticity in melanoma and its contribution to invasion and metastasis.

Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University Průmyslová 595 252 42 Vestec u Prahy Czech Republic

Department of Biology Faculty of Medicine Masaryk University Kamenice 5 625 00 Brno Czech Republic

Department of Cell Biology Charles University Viničná 7 128 44 Prague Czech Republic

International Clinical Research Center St Anne's University Hospital Pekařská 53 656 91 Brno Czech Republic

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Rambow F., Marine J.-C., Goding C.R. Melanoma plasticity and phenotypic diversity: Therapeutic barriers and opportunities. Genes Dev. 2019;33:1295–1318. doi: 10.1101/gad.329771.119. PubMed DOI PMC

Goding C.R., Arnheiter H. Mitf—the First 25 Years. Genes Dev. 2019;33:983–1007. doi: 10.1101/gad.324657.119. PubMed DOI PMC

Hartman M.L., Czyz M. MITF in melanoma: Mechanisms behind its expression and activity. Cell. Mol. Life Sci. 2015;72:1249–1260. doi: 10.1007/s00018-014-1791-0. PubMed DOI PMC

Kim J.-H., Hong A.-R., Kim Y.-H., Yoo H., Kang S.-W., Chang S.E., Song Y. JNK suppresses melanogenesis by interfering with CREB-regulated transcription coactivator 3-dependent MITF expression. Theranostics. 2020;10:4017–4029. doi: 10.7150/thno.41502. PubMed DOI PMC

Falletta P., Sanchez-Del-Campo L., Chauhan J., Effern M., Kenyon A., Kershaw C.J., Siddaway R., Lisle R.J., Freter R., Daniels M.J., et al. Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. Genes Dev. 2017;31:18–33. doi: 10.1101/gad.290940.116. PubMed DOI PMC

Buscà R., Bertolotto C., Abbe P., Englaro W., Ishizaki T., Narumiya S., Boquet P., Ortonne J.P., Ballotti R. Inhibition of rho is required for CAMP-induced melanoma cell differentiation. Mol. Biol. Cell. 1998;9:1367–1378. doi: 10.1091/mbc.9.6.1367. PubMed DOI PMC

Hoek K.S., Schlegel N.C., Brafford P., Sucker A., Ugurel S., Kumar R., Weber B.L., Nathanson K.L., Phillips D.J., Herlyn M., et al. Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature. Pigment. Cell Res. 2006;19:290–302. doi: 10.1111/j.1600-0749.2006.00322.x. PubMed DOI

Vivas-García Y., Falletta P., Liebing J., Louphrasitthiphol P., Feng Y., Chauhan J., Scott D.A., Glodde N., Chocarro-Calvo A., Bonham S., et al. Lineage-restricted regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity. Mol. Cell. 2020;77:120–137.e9. doi: 10.1016/j.molcel.2019.10.014. PubMed DOI PMC

Misek S.A., Appleton K.M., Dexheimer T.S., Lisabeth E.M., Lo R.S., Larsen S.D., Gallo K.A., Neubig R.R. Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells. Oncogene. 2020;39:1466–1483. doi: 10.1038/s41388-019-1074-1. PubMed DOI PMC

Konieczkowski D.J., Johannessen C.M., Abudayyeh O., Kim J.W., Cooper Z.A., Piris A., Frederick D.T., Barzily-Rokni M., Straussman R., Haq R., et al. A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov. 2014;4:816–827. doi: 10.1158/2159-8290.CD-13-0424. PubMed DOI PMC

Verfaillie A., Imrichova H., Atak Z.K., Dewaele M., Rambow F., Hulselmans G., Christiaens V., Svetlichnyy D., Luciani F., Van Der Mooter L.L., et al. Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state. Nat. Commun. 2015;6:6683. doi: 10.1038/ncomms7683. PubMed DOI PMC

Kholmanskikh O., Van Baren N., Brasseur F., Ottaviani S., Vanacker J., Arts N., Van Der Bruggen P., Coulie P., De Plaen E. Interleukins 1α and 1β secreted by some melanoma cell lines strongly reduce expression of MITF-M and melanocyte differentiation antigens. Int. J. Cancer. 2010;127:1625–1636. doi: 10.1002/ijc.25182. PubMed DOI

Miskolczi Z., Smith M.P., Rowling E.J., Ferguson J., Barriuso J., Wellbrock C. Collagen abundance controls melanoma phenotypes through lineage-specific microenvironment sensing. Oncogene. 2018;37:3166–3182. doi: 10.1038/s41388-018-0209-0. PubMed DOI PMC

Strub T., Kobi D., Koludrovic D., Davidson I. In: Research on Melanoma—A Glimpse into Current Directions and Future Trends. Murph M., editor. IntechOpen; London, UK: 2011.

Thurber A., Douglas G., Sturm E., Zabierowski S., Smit D., Ramakrishnan S., Hacker E., Leonard J., Herlyn M., Sturm R. Inverse expression states of the BRN2 and MITF transcription factors in melanoma spheres and tumour xenografts regulate the NOTCH pathway. Oncogene. 2011;30:3036–3048. doi: 10.1038/onc.2011.33. PubMed DOI PMC

O’Connell M.P., Marchbank K., Webster M.R., Valiga A.A., Kaur A., Vultur A., Li L., Herlyn M., Villanueva J., Liu Q., et al. Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2. Cancer Discov. 2013;3:1378–1393. doi: 10.1158/2159-8290.CD-13-0005. PubMed DOI PMC

Landsberg J., Kohlmeyer J., Renn M., Bald T., Rogava M., Cron M., Fatho M., Lennerz V., Wölfel T., Hölzel M., et al. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature. 2012;490:412–416. doi: 10.1038/nature11538. PubMed DOI

Mehta A., Kim Y.J., Robert L., Tsoi J., Comin-Anduix B., Berent-Maoz B., Cochran A.J., Economou J.S., Tumeh P.C., Puig-Saus C., et al. Immunotherapy resistance by inflammation-induced dedifferentiation. Cancer Discov. 2018;8:935–943. doi: 10.1158/2159-8290.CD-17-1178. PubMed DOI PMC

Müller J., Krijgsman O., Tsoi J., Robert L., Hugo W., Song C., Kong X., Possik P.A., Cornelissen-Steijger P.D.M., Foppen M.H.G., et al. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat. Commun. 2014;5:5712. doi: 10.1038/ncomms6712. PubMed DOI PMC

Kozar I., Margue C., Rothengatter S., Haan C., Kreis S. Many ways to resistance: How melanoma cells evade targeted therapies. Biochim. Biophys. Acta Rev. Cancer. 2019;1871:313–322. doi: 10.1016/j.bbcan.2019.02.002. PubMed DOI

Arozarena I., Wellbrock C. Phenotype plasticity as enabler of melanoma progression and therapy resistance. Nat. Rev. Cancer. 2019;19:377–391. doi: 10.1038/s41568-019-0154-4. PubMed DOI

Moustakas A., Heldin C.H. Non-smad TGF-β signals. J. Cell Sci. 2005;118:3573–3584. doi: 10.1242/jcs.02554. PubMed DOI

Moustakas A., Heldin C.-H. Dynamic control of TGF-β signaling and its links to the cytoskeleton. FEBS Lett. 2008;582:2051–2065. doi: 10.1016/j.febslet.2008.03.027. PubMed DOI

Kim J.-G., Islam R., Cho J.Y., Jeong H., Cap K.-C., Park Y., Hossain A.J., Park J.-B. Regulation of RhoA GTPase and various transcription factors in the RhoA pathway. J. Cell. Physiol. 2018;233:6381–6392. doi: 10.1002/jcp.26487. PubMed DOI

Lin C., Yao E., Zhang K., Jiang X., Croll S., Thompson-Peer K., Chuang P.-T. YAP is essential for mechanical force production and epithelial cell proliferation during lung branching morphogenesis. eLife. 2017;6:e21130. doi: 10.7554/eLife.21130. PubMed DOI PMC

Edwards D.N., Ngwa V.M., Wang S., Shiuan E., Brantley-Sieders D.M., Kim L.C., Reynolds A.B., Chen J. The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ. Sci. Signal. 2017;10:eaan4667. doi: 10.1126/scisignal.aan4667. PubMed DOI PMC

Srivastava S., Pang K.M., Iida M., Nelson M.S., Liu J., Nam A., Wang J., Mambetsariev I., Pillai R., Mohanty A., et al. Activation of EPHA2-ROBO1 heterodimer by SLIT2 attenuates non-canonical signaling and proliferation in squamous cell carcinomas. iScience. 2020;23:101692. doi: 10.1016/j.isci.2020.101692. PubMed DOI PMC

Malik A., Kanneganti T.-D. Function and regulation of IL-1α in inflammatory diseases and cancer. Immunol. Rev. 2018;281:124–137. doi: 10.1111/imr.12615. PubMed DOI PMC

Paňková D., Jobe N., Kratochvílová M., Buccione R., Brábek J., Rösel D. NG2-mediated Rho activation promotes amoeboid invasiveness of cancer cells. Eur. J. Cell Biol. 2012;91:969–977. doi: 10.1016/j.ejcb.2012.05.001. PubMed DOI

Vaškovičová K., Szabadosová E., Čermák V., Gandalovičová A., Kasalová L., Rösel D., Brábek J. PKCα promotes the mesenchymal to amoeboid transition and increases cancer cell invasiveness. BMC Cancer. 2015;15:326. doi: 10.1186/s12885-015-1347-1. PubMed DOI PMC

Dovas A., Yoneda A., Couchman J.R. PKC-α-dependent activation of RhoA by syndecan-4 during focal adhension formation. J. Cell Sci. 2006;119:2837–2846. doi: 10.1242/jcs.03020. PubMed DOI

Riesenberg S., Groetchen A., Siddaway R., Bald T., Reinhardt J., Smorra D., Kohlmeyer J., Renn M., Phung B., Aymans P., et al. MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment. Nat. Commun. 2015;6:8755. doi: 10.1038/ncomms9755. PubMed DOI PMC

Arts N., Cané S., Hennequart M., Lamy J., Bommer G., Van Den Eynde B., De Plaen E. microRNA-155, Induced by interleukin-1ß, represses the expression of microphthalmia-associated transcription factor (MITF-M) in melanoma cells. PLoS ONE. 2015;10:e0122517. doi: 10.1371/journal.pone.0122517. PubMed DOI PMC

Soustek M.S., Balsa E., Barrow J.J., Jedrychowski M., Vogel R., Gygi S.P., Puigserver P. Inhibition of the ER stress IRE1α inflammatory pathway protects against cell death in mitochondrial complex I mutant cells. Cell Death Dis. 2018;9:658. doi: 10.1038/s41419-018-0696-5. PubMed DOI PMC

Chaudhari N., Talwar P., Parimisetty A., d’Hellencourt C.L., Ravanan P. A molecular web: Endoplasmic reticulum stress, inflammation, and oxidative stress. Front. Cell. Neurosci. 2014;8:213. doi: 10.3389/fncel.2014.00213. PubMed DOI PMC

Ju R.J., Stehbens S.J., Haass N.K. The role of melanoma cell-stroma interaction in cell motility, invasion, and metastasis. Front. Med. 2018;5:5. doi: 10.3389/fmed.2018.00307. PubMed DOI PMC

Paňková K., Rösel D., Novotný M., Brábek J. The molecular mechanisms of transition between mesenchymal and amoeboid invasiveness in tumor cells. Cell. Mol. Life Sci. 2009;67:63–71. doi: 10.1007/s00018-009-0132-1. PubMed DOI PMC

Kosla J., Paňková D., Plachý J., Tolde O., Bicanová K., Dvořák M., Rösel D., Brábek J. Metastasis of aggressive amoeboid sarcoma cells is dependent on Rho/ROCK/MLC signaling. Cell Commun. Signal. 2013;11:51. doi: 10.1186/1478-811X-11-51. PubMed DOI PMC

Micuda S., Rösel D., Ryska A., Brábek J. ROCK inhibitors as emerging therapeutic candidates for sarcomas. Curr. Cancer Drug Targets. 2010;10:127–134. doi: 10.2174/156800910791054202. PubMed DOI

Voller J., Zahajská L., Plíhalová L., Jeřábková J., Burget D., Pataki A.C., Kryštof V., Zatloukal M., Brábek J., Rösel D., et al. 6-substituted purines as ROCK inhibitors with anti-metastatic activity. Bioorg. Chem. 2019;90:103005. doi: 10.1016/j.bioorg.2019.103005. PubMed DOI

Cantelli G., Orgaz J.L., Rodriguez-Hernandez I., Karagiannis P., Maiques O., Matias-Guiu X., Nestle F.O., Marti R.M., Karagiannis S.N., Sanz-Moreno V. TGF-β-induced transcription sustains amoeboid melanoma migration and dissemination. Curr. Biol. 2015;25:2899–2914. doi: 10.1016/j.cub.2015.09.054. PubMed DOI PMC

Georgouli M., Herraiz C., Crosas-Molist E., Fanshawe B., Maiques O., Perdrix A., Pandya P., Rodriguez-Hernandez I., Ilieva K.M., Cantelli G., et al. Regional activation of myosin II in cancer cells drives tumor progression via a secretory cross-talk with the immune microenvironment. Cell. 2019;176:757–774.e23. doi: 10.1016/j.cell.2018.12.038. PubMed DOI PMC

Merta L., Gandalovičová A., Čermák V., Dibus M., Gutschner T., Diederichs S., Rösel D., Brábek J. Increased level of long non-coding RNA MALAT1 is a common feature of amoeboid invasion. Cancers. 2020;12:1136. doi: 10.3390/cancers12051136. PubMed DOI PMC

Sanz-Moreno V., Gaggioli C., Yeo M., Albrengues J., Wallberg F., Viros A., Hooper S., Mitter R., Féral C.C., Cook M., et al. ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell. 2011;20:229–245. doi: 10.1016/j.ccr.2011.06.018. PubMed DOI

Sanz-Moreno V., Gadea G., Ahn J., Paterson H., Marra P., Pinner S., Sahai E., Marshall C.J. Rac activation and inactivation control plasticity of tumor cell movement. Cell. 2008;135:510–523. doi: 10.1016/j.cell.2008.09.043. PubMed DOI

Karaman M.W., Herrgard S., Treiber D.K., Gallant P., Atteridge C.E., Campbell B.T., Chan K.W., Ciceri P., Davis M.I., Edeen P.T., et al. A quantitative analysis of kinase inhibitor selectivity. Nat. Biotechnol. 2008;26:127–132. doi: 10.1038/nbt1358. PubMed DOI

Bain J., Plater L., Elliott M., Shpiro N., Hastie C.J., Mclauchlan H., Klevernic I., Arthur J.S.C., Alessi D.R., Cohen P. The selectivity of protein kinase inhibitors: A further update. Biochem. J. 2007;408:297–315. doi: 10.1042/BJ20070797. PubMed DOI PMC

Palušová V., Renzová T., Verlande A., Vaclová T., Medková M., Cetlová L., Sedláčková M., Hříbková H., Slaninová I., Krutá M., et al. Dual targeting of BRAF and mTOR signaling in melanoma cells with pyridinyl imidazole compounds. Cancers. 2020;12:1516. doi: 10.3390/cancers12061516. PubMed DOI PMC

Yang C., Zhu Z., Tong B.C.-K., Iyaswamy A., Xie W.-J., Zhu Y., Sreenivasmurthy S.G., Senthilkumar K., Cheung K.-H., Song J.-X., et al. A stress response P38 MAP kinase inhibitor SB202190 promoted TFEB/TFE3-dependent autophagy and lysosomal biogenesis independent of P38. Redox Biol. 2020;32:101445. doi: 10.1016/j.redox.2020.101445. PubMed DOI PMC

Čermák V., Škarková A., Merta L., Rösel D., Brábek J. Melanoma Phenotype Switch in 3D Collagen After P38 MAPK Inhibitor Treatment. [(accessed on 7 March 2021)]; doi: 10.6084/m9.figshare.c.5215253. Available online: PubMed DOI PMC

Hemesath T.J., Steingrímsson E., McGill G., Hansen M.J., Vaught J., Hodgkinson C.A., Arnheiter H., Copeland N.G., Jenkins N.A., Fisher D.E. Microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family. Genes Dev. 1994;8:2770–2780. doi: 10.1101/gad.8.22.2770. PubMed DOI

Martina J.A., Puertollano R. Rag GTPases mediate amino acid–dependent recruitment of TFEB and MITF to lysosomes. J. Cell Biol. 2013;200:475–491. doi: 10.1083/jcb.201209135. PubMed DOI PMC

Amae S., Fuse N., Yasumoto K.I., Sato S., Yajima I., Yamamoto H., Udono T., Durlu Y.K., Tamai M., Takahashi K., et al. Identification of a novel isoform of microphthalmia-associated transcription factor that is enriched in retinal pigment epithelium. Biochem. Biophys. Res. Commun. 1998;247:710–715. doi: 10.1006/bbrc.1998.8838. PubMed DOI

Yasumoto K., Takeda K., Saito H., Watanabe K., Takahashi K., Shibahara S. Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling. EMBO J. 2002;21:2703–2714. doi: 10.1093/emboj/21.11.2703. PubMed DOI PMC

Čermák V., Gandalovičová A., Merta L., Harant K., Rösel D., Brábek J. High-throughput transcriptomic and proteomic profiling of mesenchymal-amoeboid transition in 3D collagen. Sci. Data. 2020;7:1–11. doi: 10.1038/s41597-020-0499-2. PubMed DOI PMC

Clark E.A., Golub T.R., Lander E.S., Hynes R.O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature. 2000;406:532–535. doi: 10.1038/35020106. PubMed DOI

Kozlowski J.M., Fidler I.J., Hanna N., Hart I.R. A human melanoma line heterogeneous with respect to metastatic capacity in athymic nude mice. J. Natl. Cancer Inst. 1984;72:913–917. doi: 10.1093/jnci/72.4.913. PubMed DOI

Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J. 2011;17:10–12. doi: 10.14806/ej.17.1.200. DOI

Dobin A., Davis C.A., Schlesinger F., Drenkow J., Zaleski C., Jha S., Batut P., Chaisson M., Gingeras T.R. STAR: Ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21. doi: 10.1093/bioinformatics/bts635. PubMed DOI PMC

Čermák V., Gandalovičová A., Merta L., Rösel D., Brábek J. RNA-Seq Of Human Melanoma Cell Line A375m2 Treated with SB202190 or BIRB796 against DMSO-Treated Controls. [(accessed on 28 November 2020)]; Available online: https://identifiers.org/arrayexpress:E-MTAB-9273.

Bustin S.A., Benes V., Garson J.A., Hellemans J., Huggett J., Kubista M., Mueller R., Nolan T., Pfaffl M.W., Shipley G.L., et al. The MIQE guidelines: Minimum information for publication of quantitative real-time PCR experiments. Clin. Chem. 2009;55:611–622. doi: 10.1373/clinchem.2008.112797. PubMed DOI

Vandesompele J., De Preter K., Pattyn F., Poppe B., Van Roy N., De Paepe A., Speleman F. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:0034. doi: 10.1186/gb-2002-3-7-research0034. PubMed DOI PMC

Perkins J.R., Dawes J.M., McMahon S.B., Bennett D.L.H., Orengo C., Kohl M. ReadqPCR and NormqPCR: R packages for the reading, quality checking and normalisation of RT-QPCR quantification cycle (Cq) data. BMC Genom. 2012;13:296. doi: 10.1186/1471-2164-13-296. PubMed DOI PMC

Benjamini Y., Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J. R. Stat. Soc. Ser. B. 1995;57:289–300. doi: 10.1111/j.2517-6161.1995.tb02031.x. DOI

Čermák V., Gandalovičová A., Merta L., Fučíková J., Špíšek R., Rösel D., Brábek J. RNA-seq of macrophages of amoeboid or mesenchymal migratory phenotype due to specific structure of environment. Sci. Data. 2018;5:180198. doi: 10.1038/sdata.2018.198. PubMed DOI PMC

Kuleshov M.V., Jones M.R., Rouillard A.D., Fernandez N.F., Duan Q., Wang Z., Koplev S., Jenkins S.L., Jagodnik K.M., Lachmann A., et al. Enrichr: A comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44:W90–W97. doi: 10.1093/nar/gkw377. PubMed DOI PMC

Folberg R., Arbieva Z., Moses J., Hayee A., Sandal T., Kadkol S.H., Lin A.Y., Valyi-Nagy K., Setty S., Leach L., et al. Tumor cell plasticity in uveal melanoma: Microenvironment directed dampening of the invasive and metastatic genotype and phenotype accompanies the generation of vasculogenic mimicry patterns. Am. J. Pathol. 2006;169:1376–1389. doi: 10.2353/ajpath.2006.060223. PubMed DOI PMC

Molbiotools Multiple List Comparator. [(accessed on 4 March 2021)]; Available online: http://www.molbiotools.com/listcompare.html.

Andrews S. FastQC: A Quality Control Tool for High Throughput Sequence Data. [(accessed on 21 November 2020)]; Available online: http://www.bioinformatics.babraham.ac.uk/projects/fastqc/

Love M.I., Huber W., Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550. doi: 10.1186/s13059-014-0550-8. PubMed DOI PMC

Widmer D.S., Cheng P.F., Eichhoff O.M., Belloni B.C., Zipser M.C., Schlegel N.C., Javelaud D., Mauviel A., Dummer R., Hoek K.S. Systematic classification of melanoma cells by phenotype-specific gene expression mapping. Pigment. Cell Melanoma Res. 2012;25:343–353. doi: 10.1111/j.1755-148X.2012.00986.x. PubMed DOI

Han H., Cho J.-W., Lee S.-Y., Yun A., Kim H., Bae D., Yang S., Kim C.Y., Lee M., Kim E., et al. TRRUST v2: An expanded reference database of human and mouse transcriptional regulatory interactions. Nucleic Acids Res. 2018;46:D380–D386. doi: 10.1093/nar/gkx1013. PubMed DOI PMC

Tirosh I., Izar B., Prakadan S.M., Wadsworth M.H., Treacy D., Trombetta J.J., Rotem A., Rodman C., Lian C., Murphy G., et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-Seq. Science. 2016;352:189–196. doi: 10.1126/science.aad0501. PubMed DOI PMC

Jeffs A.R., Glover A.C., Slobbe L.J., Wang L., He S., Hazlett J.A., Awasthi A., Woolley A.G., Marshall E.S., Joseph W.R., et al. A gene expression signature of invasive potential in metastatic melanoma cells. PLoS ONE. 2009;4:e8461. doi: 10.1371/journal.pone.0008461. PubMed DOI PMC

Rodriguez-Hernandez I., Maiques O., Kohlhammer L., Cantelli G., Perdrix-Rosell A., Monger J., Fanshawe B., Bridgeman V.L., Karagiannis S.N., Penin R.M., et al. WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion. Nat. Commun. 2020;11:1–20. doi: 10.1038/s41467-020-18951-2. PubMed DOI PMC

Arozarena I., Bischof H., Gilby D., Belloni B., Dummer R., Wellbrock C. In melanoma, beta-catenin is a suppressor of invasion. Oncogene. 2011;30:4531–4543. doi: 10.1038/onc.2011.162. PubMed DOI PMC

Parri M., Taddei M.L., Bianchini F., Calorini L., Chiarugi P. EphA2 reexpression prompts invasion of melanoma cells shifting from mesenchymal to amoeboid-like motility style. Cancer Res. 2009;69:2072–2081. doi: 10.1158/0008-5472.CAN-08-1845. PubMed DOI

Microtubule-associated NAV3 regulates invasive phenotypes in glioblastoma cells

RNA-seq Characterization of Melanoma Phenotype Switch in 3D Collagen after p38 MAPK Inhibitor Treatment