Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Repression of stress-induced LINE-1 expression protects cancer cell populations from lethal drug-exposures [ATAC-Seq]

ABSTRACT: Establishing and maintaining phenotypic heterogeneity within cell and organismal populations is an evolutionarily conserved strategy that ensures survival of the population following stressful exposures. We previously identified a transient, reversible, drug-tolerant cancer cell subpopulation that survives otherwise lethal drug exposures. Here we show that these drug-tolerant persisters (DTPs) assume a highly heterochromatic state, which requires factors that modify or bind trimethylated H3 lysine 9 (H3K9me3). The increased H3K9me3 in DTPs is largely restricted to evolutionarily young Long Interspersed Repeat elements (LINEs). This transcriptionally repressive state, which decreases the expression of these retrotransposable elements, is critical for DTP survival, and disruption of this heterochromatic state results in re-expression of LINE elements and ablation of this subpopulation. Together, these findings establish a role for epigenetic silencing of transposable elements as a population survival strategy to maintain genomic integrity in subpopulations of cancer cells during lethal drug exposures.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73874 | GEO | 2017/07/03

SECONDARY ACCESSION(S): PRJNA301678

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Drug-tolerant cancer cell persisters survive lethal exposures by silencing transposable elements [ChIP-Seq]

Project description:Establishing and maintaining phenotypic heterogeneity within cell and organismal populations is an evolutionarily conserved strategy that ensures survival of the population following stressful exposures. We previously identified a transient, reversible, drug-tolerant cancer cell subpopulation that survives otherwise lethal drug exposures. Here we show that these drug-tolerant persisters (DTPs) assume a highly heterochromatic state, which requires factors that modify or bind trimethylated H3 lysine 9 (H3K9me3). The increased H3K9me3 in DTPs is largely restricted to evolutionarily young Long Interspersed Repeat elements (LINEs). This transcriptionally repressive state, which decreases the expression of these retrotransposable elements, is critical for DTP survival, and disruption of this heterochromatic state results in re-expression of LINE elements and ablation of this subpopulation. Together, these findings establish a role for epigenetic silencing of transposable elements as a population survival strategy to maintain genomic integrity in subpopulations of cancer cells during lethal drug exposures.

2017-07-03 | GSE74179 | GEO

Colorectal cancer cells possess an equipotent capacity to enter a reversible diapause-like state to survive chemotherapy

Project description:Cancer cells enter a reversible drug tolerant persister (DTP) state to evade death from chemotherapies and targeted agents. It is increasingly appreciated that DTPs are an important driver of therapy failure and tumor relapse. We combined cellular barcoding and mathematical modeling in patient-derived colorectal cancer models to identify and characterize DTPs in response to chemotherapy. Barcode analysis revealed no loss in clonal complexity of tumors that entered the DTP state and recurred following treatment cessation. Our data fits a mathematical model where all cancer cells, and not a small subpopulation, possess an equipotent capacity to become DTPs. Mechanistically, we determined that DTPs display remarkable transcriptional and functional similarities to diapause, a reversible state of suspended embryonic development triggered by unfavorable environmental conditions. Our study provides insight into how cancer cells use a developmentally conserved mechanism to drive the DTP state pointing to novel therapeutic opportunities to target DTPs.

2021-01-07 | GSE145356 | GEO

Functional screening implicates miR-371-3p and peroxiredoxin 6 in reversible tolerance to cancer drugs [SPR899]

Project description:Acquired resistance to cancer drug therapies almost always occurs in advanced-stage patients even following a significant response to treatment. In addition to mutational mechanisms, various non-mutational resistance mechanisms have now been recognized. We previously described a chromatin-mediated subpopulation of reversibly drug-tolerant persisters (DTPs) that is dynamically maintained within a wide variety of tumor cell populations. Here, we explored a potential role for microRNAs in such transient drug tolerance. Functional screening of 879 human microRNAs revealed miR-371-3p as a potent suppressor of drug tolerance. PRDX6 (peroxiredoxin 6) was identified as a key target of miR-371-3p in establishing drug tolerance by regulating PLA2/PKCÎ± activity and reactive oxygen species. PRDX6 expression is associated with poor prognosis in cancers of multiple tissue origins. These findings implicate miR-371-3p as a suppressor of PRDX6 and suggest that co-targeting of PRDX6 or modulating miR-371-3p expression together with targeted cancer therapies may delay or prevent acquired drug resistance. Drug tolerant persisters (DTPs) generated in response to erlotinib treatment were the basis for RNA extraction and hybridization on Affymetrix microarrays. PC9 cells were treated with DMSO or Erlotinib for 9 days to generate DTPs, then RNA was isolated for analyzing the differential gene expression pattern in DTPs compared to parental cells.

2016-08-01 | E-GEOD-83118 | biostudies-arrayexpress

The Ontogeny and Vulnerabilities of Lapatinib Drug Tolerant Persisters [NPY1R]

Project description:Despite significant advances in HER2-targeted therapies, therapeutic resistance in HER2-positive (HER2+) breast cancer remains a significant clinical problem, especially in the metastatic setting. “Drug tolerant persisters” (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in several cancer models, but DTPs for HER2-targeted TKIs (e.g., lapatinib, neratinib, tucatinib) have not been characterized extensively. Here, we report that HER2+ER+ and HER2+ER- breast cancer lines give rise to distinct types of “lapatinib-DTPs,” characterized by different transcriptional programs and sensitivity to lapatinib/anti-estradiol combination. Lapatinib-DTPs from HER2+/ER+ cells rewire the PI3K/AKT/mTORC1 pathway via transcriptional induction of SGK3 to enable AKT-independent mTORC1 activation and survival. Lentiviral barcoding experiments, combined with single cell RNA-sequencing, suggest that HER2+ cells stochastically cycle through a cell state (“pre-DTP”) capable of transition to DTPs. Collectively, our results provide insight into DTP ontogeny and therapeutic vulnerabilities.

2021-12-31 | GSE155227 | GEO

The Ontogeny and Vulnerabilities of Lapatinib Drug Tolerant Persisters [Parental (P) vs. Drug-Tolerant Persister (DTP)]

2021-12-31 | GSE155341 | GEO

Proteomic analyses identify a novel role for EZH2 in the initiation of cancer cell drug tolerance

Project description:Acquisition of drug resistance remains a chief impediment to successful cancer therapy, and we previously described a transient drug-tolerant cancer cell population (DTPs) whose survival is in part dependent on the activities of the histone methyltransferases G9a/EHMT2 and EZH2, the latter being the catalytic component of the polycomb repressive complex 2 (PRC2). Here, we applied multiple proteomic techniques to better understand the role of these HMTs in the establishment of the DTP state. Proteome-wide comparisons of lysine methylation patterns revealed that DTPs have increased methylation on K116 of PRC member Jarid2, an event that helps stabilize and recruit PRC2 to chromatin. We also found that EZH2, in addition to methylating histone H3K27, also methylates G9a at K185, and that methylated G9a better recruits repressive complexes to chromatin; similar to complexes recruited by histone H3 methylated at K9. Finally, a detailed histone posttranslational modification (PTM) analysis shows that EZH2, either directly or through its ability to methylate G9a, alters H3K9 methylation in the specific context of H3 serine10 phosphorylation, and primarily in a cancer cell subpopulation that serves as DTP precursors. We also show that combinations of histone PTMs recruit a different set of complexes to chromatin, shedding light on the temporal mechanisms that contribute to drug tolerance.

2020-01-24 | MSV000084838 | MassIVE

Ontogeny and Vulnerability of Lapatinib Drug-Tolerant Persisters in HER2-positive Breast Cancer

Project description:Despite advances in HER2-targeted therapeutics, resistance remains a significant clinical problem in HER2-positive (HER2+) breast cancer, especially in the metastatic setting. Drug-tolerant persisters (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in several cancer models, but DTPs for HER2-targeted TKIs have not been characterized extensively. We found that upon treatment with the TKI lapatinib, HER2+ breast cancer lines yielded DTPs with luminal-like or mesenchymal-like transcriptional programs and differential sensitivity to lapatinib/anti-estradiol combinations. Lentiviral barcoding and single cell RNA-sequencing indicate that HER2+/ER+ cells cycle stochastically through a pre-DTP state, characterized by a G0-like signature, which uniquely gives rise to DTPs upon lapatinib exposure.

2021-12-13 | GSE156246 | GEO

841fd1a1-3b4c-4aba-9193-0eb3a987236c - samples

Project description:Cancer cells enter a reversible drug tolerant persister (DTP) state to evade death from both chemotherapies and targeted agents. It is increasingly appreciated that the DTP state is an important driver of therapy failure and tumor relapse. We combined cellular barcoding and mathematical modeling in patient-derived colorectal cancer xenograft models to identify and characterize the cancer cells capable of generating DTPs in response to standard-of-care chemotherapy. Barcode analysis revealed no loss in clonal complexity of tumors that entered the DTP state and recurred following treatment cessation. Our data fits a mathematical model in which all cancer cells, and not a small subpopulation, possess an equipotent capacity to enter the DTP state. Mechanistically, we determined that DTPs display remarkable transcriptional and functional similarities to diapause, a reversible state of suspended embryonic development triggered by unfavorable environmental conditions. Our study provides new insights into how cancer cells use a developmentally conserved mechanism to drive the DTP state pointing to novel therapeutic opportunities to target diapause-like DTPs.

| EGAD00001006849 | EGA

Colorectal cancer cells possess an equipotent capacity to enter a developmental pausing-like state to survive chemotherapy

| EGAS00001004773 | EGA

Mutation independent activation of the Notch pathway is associated with Lapatinib resistance in Her2+ breast cancer cell lines

Project description:We compared untreated HCC1419 cells with Lapatinib resistant HCC1419 cells that were either treated with Lapatinib for only 9 days before harvesting (drug tolerant persisters, DTPs) or were growing in the presence of Lapatinib (>70 days) (drug tolerant expanded persisters, DTEPs). We show that the Notch pathway is significantly over-expressed in DTEPs when compared to untreated cells.

2015-01-15 | GSE62074 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data