Adaptive resistance to targeted therapy such as BRAF inhibitors represents in melanoma a major drawback to this otherwise powerful treatment. Some of the underlying molecular mechanisms have recently been described: hyperactivation of the BRAF-MAPK pathway, of the AKT pathway, of the TGF/EGFR/PDGFRB pathway, or the low MITF/AXL ratio. Nevertheless, the phenomenon of early resistance is still not clearly understood. In this report, we show that knockdown of neural crest-associated gene ID3 increases the melanoma sensitivity to vemurafenib short-term treatment. In addition, we observe an ID3-mediated regulation of cell migration and of the expression of resistance-associated genes such as SOX10 and MITF. In sum, these data suggest ID3 as a new key actor of melanoma adaptive resistance to vemurafenib and as a potential drug target. Molecular mechanisms that are responsible for the development of human skin epithelial cells are not completely understood so far. As a consequence, the efficiency to establish a pure skin epithelial cell population from human induced pluripotent stem cells (hiPSC) remains poor. Using an approach including RNA interference and high-throughput imaging of early epithelial cells, we could identify candidate kinases which are involved in skin epithelial differentiation. Among them, we found HIPK4 to be an important inhibitor of this process. Indeed, its silencing increased the amount of generated skin epithelial precursors, increased the amount of generated keratinocytes and improved growth and differentiation of organotypic cultures, allowing for the formation of a denser basal layer and stratification with the expression of several keratins. Our data bring substantial input in the regulation of human skin epithelial differentiation and for improving differentiation protocols from pluripotent stem cells.
New role of ID3 in melanoma adaptive drug-resistance.
Cell line, Treatment
View SamplesMDSC (myeloid-derived suppressor cells) can be differentiated in vitro using IL-6 and GM-CSF. To identify the specific role of IL-6 in this process, we used microarray to compare MDSC differentiated with IL-6 and GM-CSF to MDSC differentiated with GM-CSF alone. We have found genes and pathways that are up- or downregulated when IL-6 is present.
IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma.
Specimen part, Treatment
View SamplesThe objective of this experiment was to test the effect, at a transcrptomic level, of lymphotoxin-beta receptor activation in HBV-infected differentiated HepaRG cells
Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA.
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