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Gene expression signature of vemurafenib resistance in WM989 and WM983B melanoma cells

ABSTRACT: Therapies targeting signaling molecules mutated in cancers can often have striking short-term effects, but the emergence of resistant cancer cells is a major barrier to full cures. Resistance can sometimes result from a secondary mutations in rare cells, but other times, there is no clear genetic cause, raising leaving the possibility of non-genetic rare cell variability. Here, we show that melanoma cells can display profound transcriptional variability at the single cell level that predicts which cells will ultimately resist drug treatment. This variability involves semi-coordinated transcription of a number of resistance markers at high levels in a very small percentage of cells. The addition of drug then induces an epigenetic reprogramming in these cells, converting the transient transcriptional state to a stably resistant state. This reprogramming begins withis a progressive process consisting of a loss of SOX10-mediated differentiation followed by activation of new signaling pathways, partially mediated by activity of Jun-AP-1 and TEAD. Our work reveals the multistage nature of the acquisition of drug resistance and provides a framework for understanding resistance dynamics. We find that other cell types also exhibit sporadic expression of many of these same marker genes, suggesting the existence of a general rare-cell expression program.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97681 | GEO | 2017/04/13

SECONDARY ACCESSION(S): PRJNA382674

REPOSITORIES: GEO

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Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance [ATAC-seq]

Project description:Therapies targeting signaling molecules mutated in cancers can often have striking short-term effects, but the emergence of resistant cancer cells is a major barrier to full cures. Resistance can sometimes result from a secondary mutations in rare cells, but other times, there is no clear genetic cause, raising leaving the possibility of non-genetic rare cell variability. Here, we show that melanoma cells can display profound transcriptional variability at the single cell level that predicts which cells will ultimately resist drug treatment. This variability involves semi-coordinated transcription of a number of resistance markers at high levels in a very small percentage of cells. The addition of drug then induces an epigenetic reprogramming in these cells, converting the transient transcriptional state to a stably resistant state. This reprogramming begins withis a progressive process consisting of a loss of SOX10-mediated differentiation followed by activation of new signaling pathways, partially mediated by activity of Jun-AP-1 and TEAD. Our work reveals the multistage nature of the acquisition of drug resistance and provides a framework for understanding resistance dynamics. We find that other cell types also exhibit sporadic expression of many of these same marker genes, suggesting the existence of a general rare-cell expression program.

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Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance [RNA-seq]

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Vemurafenib resistance selects for highly malignant brain and lung-metastasizing melanoma cells

Project description:V600E being the most common mutation in BRAF, leads to constitutive activation of the MAPK signaling pathway. The majority of V600E BRAF positive melanoma patients treated with the BRAF inhibitor vemurafenib showed initial good clinical responses but relapsed due to acquired resistance to the drug. The aim of the present study was to identify possible biomarkers associated with the emergence of drug resistant melanoma cells. To this end we analyzed the differential gene expression of vemurafenib-sensitive and vemurafenib resistant brain and lung metastasizing melanoma cells. The major finding of this study is that the in vitro induction of vemurafenib resistance in melanoma cells is associated with an increased malignancy phenotype of these cells. Resistant cells expressed higher levels of genes coding for cancer stem cell markers (JARID1B, CD271 and Fibronectin) as well as genes involved in drug resistance (ABCG2), cell invasion and promotion of metastasis (MMP-1 and MMP-2). We also showed that drug-resistant melanoma cells adhere better to and transmigrate more efficiently through lung endothelial cells than drug-sensitive cells. The former cells also alter their microenvironment in a different manner from that of drug-sensitive cells. Biomarkers and molecular mechanisms associated with drug resistance may serve as targets for therapy of drug-resistant cancer.

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Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance

Project description:Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance

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Variability within rare cell states enables multiple paths towards drug resistance [WM989_WM983b]

Project description:Molecular differences between individual cells can lead to dramatic differences in cell fate, such as the difference between death versus survival of cancer cells upon treatment with anti-cancer drugs. Despite some progress, these originating differences have largely remained hidden due to the difficulty in determining precisely what variable molecular features lead to which cellular fates. Here, we trace drug-resistant cell fates back to differences in the molecular profiles of their drug-naive melanoma precursors, revealing a rich substructure of variability underlying a number of resistant phenotypes at the single cell level. We make these connections using Rewind, a methodology that combines genetic barcoding with an RNA-based readout to directly capture rare cells that give rise to cellular behaviors of interest. We performed extensive single cell analysis to identify differences in gene expression and MAP-kinase signaling that mark a rare population of drug-naive cells (initial frequency of ~1:1000-1:10,000 cells) that ultimately gives rise to drug resistant clones. We demonstrate that this rare subpopulation has rich substructure and is composed of several distinct subpopulations, and the molecular differences between these subpopulations predict future differences in phenotypic behavior, such as the ultimate proliferative capacity of drug resistant cells. Similarly, we show that treatments that modify the frequency of resistance can allow otherwise non-resistant cells in the drug-naive population to become resistant, and that these new populations are marked by the variable expression of distinct genes. Together, our results reveal the presence of hidden, rare-cell variability that can underlie a range of latent phenotypic outcomes upon drug exposure.

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Variability within rare cell states enables multiple paths towards drug resistance [WM989_DOT1Li]

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Profiling melanoma cell line M14 treated with vemurafenib

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Homo sapiens

Project description:Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance [RNA-seq]

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Homo sapiens

Project description:Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance [ATAC-seq]

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Time-series RNA-seq experiment performed on 10 melanoma cell lines treated with BRAF inhibitor vemurafenib.

Project description:BRAF targeted drug vemurafenib have shown very good clinical benefit in melanoma patient containing BRAF V600E mutation. However, resistance always occurs in patient. Early stage of the resistance development require the tumor cell adapted to the targeted drug. We are trying to study the kinetic of melanoma cell adaptation towards vemurafenib. 10 melanoma cell lines with BRAF mutation are treated with targeted therapy vemurafenib. RNA-seq samples are collected after drug treatment for different time (day3 and day21) to compare with DMSO-treated control samples for each cell line. Except innate resistant cell line M381, all other cell lines shows inhibition of proliferation. However, a small cluster of cell lines (M397, M229 and M263) shows some other unique transcriptomic change. For cell line M397, M229 and M263, we also collected the RNA-seq data for long-term (73day/90day) drug treatment condition where the cells developed resistance to vemurafenib treatment. Dedifferentiation is enriched in these unique transcriptomic change within these 3 cell lines. Similar cell state dedifferentiation phenomenon is also reported to cause resistance towards immunotherpay where the resistant de-differentiated melanoma cells are induced by TNF which is secreted by tumor-infiltrating T cells. We also treat our cultured melanoma cells with TNF and collected the treated sample for RNA-seq experiment.

2019-06-22 | E-MTAB-5493 | biostudies-arrayexpress

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