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Human dermal fibroblast reprogramming: compact and differentiated colonies during maturation phase

ABSTRACT: Transcriptional profiling of reprogrammed cells at day 20 post-transduction comparing compact and differentiated colonies with established induced Pluripotent Stem Cells (iPSC) generated from human dermal fibroblasts (HDF). This study focused in the identification of upregulated transcription factors related to early developmental processes, particularly during primitive streak formation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103491 | GEO | 2017/09/06

SECONDARY ACCESSION(S): PRJNA401772

REPOSITORIES: GEO

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Project description:Background: Vemurafenib (PLX4032) is one of the most frequently used treatments for late-stage melanoma patients with the BRAFV600E mutation; however, acquired resistance to the drug remains as a major challenge. It remains to be determined whether off-target effects of the vemurafenib on normal stroma components could reshape the tumor microenvironment in a way that contributes to cancer progression and drug resistance. Methods: By using temporary-resolved RNA- and ATAC-seq, we studied the early molecular changes induced by vemurafenib in human dermal fibroblast (HDF), a main stromal component in melanoma and other tumors with high prevalence of BRAFV600 mutations. Results: Transcriptomics analyses revealed a stepwise up-regulation of proliferation signatures, together with a down-regulation of autophagy and proteolytic processes. The gene expression changes in HDF strongly correlated in an inverse way with those in BRAFV600E mutant malignant melanoma (MaMel) cell lines, consistent with the observation of a paradoxical effect of vemurafenib, leading to hyperphosphorylation of MEK1/2 and ERK1/2. The transcriptional changes in HDF were not strongly determined by alterations in chromatin accessibility; rather, an already permissive chromatin landscape seemed to facilitate the early accessibility to MAPK/ERK-regulated transcription factor binding sites. Combinatorial treatment with the MEK inhibitor trametinib did not preclude the paradoxical activation of MAPK/ERK signaling in HDF. When administered together, vemurafenib partially compensated the reduction in cell viability and proliferation induced by trametinib. These paradoxical changes were restrained by using the third generation BRAF inhibitor PLX8394, a so-called paradox breaker compound. However, the advantageous effects on HDF during combination therapies were also lost. Conclusion: Vemurafenib induces paradoxical changes on HDF, which are allowed by a permissive chromatin landscape. These changes might provide an advantage during combination therapies, by compensating the toxicity induced in stromal cells by less specific MAPK/ERK inhibitors. Our results highlight the relevance of evaluating the effects of the drugs on non-transformed stromal components, carefully considering the implications of their administration either as mono- or combination therapies.

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Human dermal fibroblast reprogramming: compact and differentiated colonies during maturation phase

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