Drug tolerant persisters in erlotinib treated EGFR-mutated lung adenocarcinoma arise from pre-existing tumor cells and survive in an adapted stromal microenvironment [RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE199716 | GEO | 2022/12/21
REPOSITORIES: GEO
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Project description:Targeted therapies require life-long treatment, as drug discontinuation invariably leads to tumor recurrence. Recurrence is thought to mainly be driven by minor subpopulations of drug tolerant persister (DTP) cells that survive the cytotoxic drug effect. In lung cancer, DTP studies have mainly been conducted using tumor cell line models. We conducted an in vivo DTP study using a lung adenocarcinoma (LUAD) patient-derived xenograft (PDX) tumor driven by an epidermal growth factor receptor (EGFR) mutation. Daily treatment of tumor-bearing mice for 5-6 weeks markedly shrunk the tumors and generated DTPs, which were analyzed by bulk population transcriptome.
2022-12-21 | GSE198672 | GEO
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
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
Project description:Non-genetic mechanisms have recently emerged as important drivers of therapy failure in cancer, where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment. While most cancer persisters, like their bacterial counterparts, remain arrested in the presence of drug, a rare subset of cancer persisters can re-enter the cell cycle under constitutive drug treatment. Little is known about the non-genetic mechanisms that enable cancer persisters to simultaneously resist therapy and maintain proliferative capacity in the presence of drug. To address this, we developed Watermelon, a new high-complexity expressed barcode lentiviral library for simultaneous tracing each cell's clonal origin, proliferative state, and transcriptional state, and used it to study this rare, transiently-resistant, proliferative persister population and identify what distinguishes it from non-cycling persisters. Analysis of Watermelon-transduced cancer cell lines demonstrated that cycling and non-cycling persisters arise from different pre-existing cell lineages with distinct transcriptional and metabolic programs. The proliferative capacity of persisters is associated with an upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation in specific subpopulations of tumor cells.
2020-05-21 | GSE150949 | GEO
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
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 | GSE155341 | GEO
Project description:The Ontogeny and Vulnerabilities of Lapatinib Drug Tolerant Persisters [Parental (P) vs. Drug-Tolerant Persister (DTP)]
| PRJNA649434 | ENA
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
Project description:Observational studies from low-income countries have shown that the vaccination against diphtheria, tetanus and pertussis (DTP) is associated with excess female mortality due to infectious diseases. To investigate possible changes in gene expression after DTP vaccination, we identified a group of nine comparable West African girls, from a biobank of 356 children, who were due to receive DTP booster vaccine at age 18 months. We extracted RNA from blood samples before, and 6 weeks after, vaccination to analyse the coding transcriptome in leukocytes using expression microarrays, and ended up with information from eight girls. The data was further analysed using dedicated array pathway and network software. We aimed to study whether DTP vaccination introduced a systematic alteration in the immune system in girls. We found very few transcripts to alter systematically. Those that did mainly belonged to the interferon (IFN) signalling pathway. We scrutinized this pathway as well as the interleukin pathways. Two out of eight showed a down-regulated IFN pathway and two showed an up-regulated IFN pathway. The two with down-regulated IFN pathway had also down-regulated IL-6 pathway. In the study of networks, two of the girls stood out as not having the inflammatory response as top altered network. In conclusion, the transcriptome changes following DTP booster vaccination were subtle, but it is possible to identify sub groups that deviate from each other, mainly in the IFN response. Microarrays (Human Exon 1.0 ST Arrays (Affymetrix )) were used to compare the gene expression alteration following DTP-vaccination in 18-19 months old West African girls. The gene expression analysis was based on RNA from venous blood. The blood was drawn immediately before DTP-vaccination (baseline sample) and 6 weeks after (42 -50 days, post-vaccination sample) in a total of eight girls
2012-10-01 | E-GEOD-39017 | biostudies-arrayexpress
Project description:Drug tolerant persister (DTP) cells enter into a reversible slow-cycling state after cancer drug treatment. These cells are the living proof of response to a drug, and an interesting experimental subject for biomarker discovery. Here, we performed proteomic characterization of the breast cancer (BC) DTP cell secretome after eribulin treatment. First, we showed that eribulin induces a specific secretome in DTP cells as compared to other microtubule targeting agents. Then, we selected and functionally validated growth differentiation factor 15 (GDF15) as a protein significantly over-secreted upon eribulin treatment. Interestingly, GDF15 expression is low/absent in cells that are sensitive to eribulin, strongly upregulated during the response to the drug, and downregulated when stable resistance is ultimately established. Proteomic results were confirmed in 3D-cell culture models using BC cells lines and PDXs, as well as in a TNBC in vivo model. Unexpectedly, despite its biomarker potential for eribulin response, we found that GDF15 is also paradoxically required for survival of DTP cells, although once full resistance to eribulin is established, GDF15 expression largely disappears. Direct participation of GDF15 and its receptor GFRAL in eribulin-induction of DTPs was established by the enhanced cell killing of DTPs by eribulin seen under GDF15 and GFRAL loss of function conditions. These results pointed to a potential benefit of simultaneous targeting of GDF15/GFRAL and eribulin, and indeed we showed that combination therapy of eribulin plus an anti-GDF15 antibody kills BC-DTP cells. Our results suggest that targeting GDF15 may help eradicate DTP cells and block the onset of acquired eribulin resistance, and possibly other cytotoxic drugs. Overall, the combination of cytotoxic agents with targeted agents aimed specifically at DTP cells could be an effective therapeutic approach for metastatic breast cancer patients.
2023-01-09 | PXD034037 | Pride