Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

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 with 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: GSE97679 | GEO | 2017/04/13

SECONDARY ACCESSION(S): PRJNA382752

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

2017-04-13 | GSE97680 | GEO

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

2017-04-13 | GSE97681 | GEO

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

| PRJNA382641 | ENA

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.

2020-11-12 | GSE161299 | GEO

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

2020-11-12 | GSE161298 | GEO

Pre-determined diversity in resistant fates emerges from homogenous cells after anti-cancer drug treatment

Project description:Even amongst genetically identical cancer cells, therapy resistance often only emerges from a very small subset of those cells. Much effort has gone into uncovering the molecular differences in rare individual cells in the initial population that may allow certain cells to become therapy resistant; however, comparatively little is known about variability in the resistant outcomes themselves. Here, we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically, and functionally distinct fate types. These different resistant types are largely predetermined by molecular differences between cells before addition of drug and not by extrinsic cell-specific microenvironmental factors. Changes in dose and kind of drug can, however, switch the resistant fate type of an initial cell, even resulting in the generation and elimination of certain fate types. Diversity in resistant fates was observed across several single-cell-derived cancer cell lines and types treated with a variety of drugs. Cell fate diversity as a result of variability in intrinsic cell states may be a generic feature of response to external cues.

2023-05-31 | GSE233622 | GEO

Pre-determined diversity in resistant fates emerges from homogenous cells after anti-cancer drug treatment (single-cell data)

2023-06-03 | GSE233766 | GEO

Variability within rare cell states enables multiple paths towards drug resistance.

Project description:Variability within rare cell states enables multiple paths towards drug resistance.

| PRJNA676147 | ENA

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

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

| PRJNA676154 | ENA

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

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

| PRJNA676155 | ENA