Article ; Online: Melanoma Progression Inhibits Pluripotency and Differentiation of Melanoma-Derived iPSCs Produces Cells with Neural-like Mixed Dysplastic Phenotype.
2019 Volume 13, Issue 1, Page(s) 177–192
Abstract: Melanomas are known to exhibit phenotypic plasticity. However, the role cellular plasticity plays in melanoma tumor progression and drug resistance is not fully understood. Here, we used reprogramming of melanocytes and melanoma cells to induced ... ...
| Abstract | Melanomas are known to exhibit phenotypic plasticity. However, the role cellular plasticity plays in melanoma tumor progression and drug resistance is not fully understood. Here, we used reprogramming of melanocytes and melanoma cells to induced pluripotent stem cell (iPSCs) to investigate the relationship between cellular plasticity and melanoma progression and mitogen-activated protein kinase (MAPK) inhibitor resistance. We found that melanocyte reprogramming is prevented by the expression of oncogenic BRAF, and in melanoma cells harboring oncogenic BRAF and sensitive to MAPK inhibitors, reprogramming can be restored by inhibition of the activated oncogenic pathway. Our data also suggest that melanoma tumor progression acts as a barrier to reprogramming. Under conditions that promote melanocytic differentiation of fibroblast- and melanocyte-derived iPSCs, melanoma-derived iPSCs exhibited neural cell-like dysplasia and increased MAPK inhibitor resistance. These data suggest that iPSC-like reprogramming and drug resistance of differentiated cells can serve as a model to understand melanoma cell plasticity-dependent mechanisms in recurrence of aggressive drug-resistant melanoma. |
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| MeSH term(s) | Biomarkers, Tumor ; Cell Differentiation ; Cell Line, Tumor ; Cell Plasticity ; Cellular Reprogramming/drug effects ; Cellular Reprogramming/genetics ; Disease Progression ; Drug Resistance, Neoplasm/genetics ; Gene Expression ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Induced Pluripotent Stem Cells/pathology ; Melanocytes/metabolism ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Mitogen-Activated Protein Kinases/antagonists & inhibitors ; Mutation ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Phenotype ; Protein Kinase Inhibitors/pharmacology |
| Chemical Substances | Biomarkers, Tumor ; Protein Kinase Inhibitors ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) |
| Language | English |
| Publishing date | 2019-06-20 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. |
| ZDB-ID | 2720528-9 |
| ISSN | 2213-6711 ; 2213-6711 |
| ISSN (online) | 2213-6711 |
| ISSN | 2213-6711 |
| DOI | 10.1016/j.stemcr.2019.05.018 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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