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Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly-dividing de-differentiated state

ABSTRACT: Treatment of BRAF-mutant melanomas with MAP-kinase pathway inhibitors is paradigmatic of the promise of precision cancer therapy but also highlights problems with drug resistance that limit patient benefit. We use live-cell imaging, single-cell analysis and molecular profiling to show that exposure of tumor cells to RAF/MEK inhibitors elicits a heterogeneous response in which some cells die, some arrest and a remaining fraction adapts to drug. Drug-adapted cells up-regulate markers of the neural crest (e.g. NGFR), a melanocyte precursor, and grow slowly. To identify genes associated with acquisition of the slowly-cycling, vemurafenib-adapted state, we performed RNA sequencing (RNA-seq) on COLO858 cells (that show the slowly-cycling phenotype) exposed to drug for 24 and 48 h; drug-treated MMACSF cells served as a control. Transcriptional profiling implicates a c-Jun/ECM/FAK/Src cascade in adaptive resistance to RAF inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE87641 | GEO | 2016/12/01

SECONDARY ACCESSION(S): PRJNA345487

REPOSITORIES: GEO

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Comparison of rapidly vs. slowly dividing CD8 T cells during acute homeostatic proliferation

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2008-07-25 | GSE8584 | GEO

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Elevating SOX2 downregulates MYC through a SOX2:MYC signaling axis and induces a slowly cycling proliferative state in human tumor cells

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Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state.

Project description: Not available

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In vitro drug screening of RAF/MEK/ERK Inhibitors in two PDA Cell Lines

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Gene Expression data for melanocyte stem cells and melanoblasts isolated from the skin of wild-type mice and B-raf and C-raf double knock-out mice

Project description:Melanocyte are melanin-producing cells located in the bottom layer of the skin's epidermis and in the hair follicle. Melanin is the pigment primarily responsible notably for skin and hair color. Our team had previously shown a role for B-raf and C-raf genes in the maintenance of melanocyte stem cells located in mice hair follicle (Valluet et al, 2012). The aim of the present project was to understand the role of B-RAF and C-RAF kinases in melanocyte stem cell self-renewal. To reach this goal, we have generated a new mouse model in which cells of the melanocyte lineage can be followed by GFP expression. We performed gene array on melanocyte stem cell B-raf+/+; C-raf+/+ and B-raf-/-; C-raf-/-in order to identify the RAF kinases target genes which are involved in melanocyte stem cell self-renewal. Moreover, to better characterize the melanocyte stem cell population, we compared its gene expression profile to the melanoblast one (melanocyte stem cell's progenitors).

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