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H3K27me3 conditions chemotolerance in triple-negative breast cancer [CUT&TAG]

ABSTRACT: Triple-negative breast cancer is associated with the worst prognosis and the highest risk of recurrence among all breast cancer subtypes1. Residual disease, formed by cancer cells persistent to chemotherapy, remains the major clinical challenge towards full cure2,3. There is now consensus that non-genetic processes contribute to chemoresistance in various tumor types, notably through the initial emergence of a reversible chemotolerant state4–6. Understanding non-genetic tumor evolution stands now as a prerequisite for the design of relevant combinatorial approaches to delay recurrence. Here we show that the repressive histone mark H3K27me3 is a determinant of cell fate under chemotherapy exposure, monitoring epigenomes, transcriptomes and lineage with single-cell resolution. We identify a reservoir of persister basal cells with EMT markers and activated TGF-β pathway leading to multiple chemoresistance phenotypes. We demonstrate that, in unchallenged cells, H3K27 methylation is a lock to the expression program of persister cells. Promoters are primed with both H3K4me3 and H3K27me3, and removing H3K27me3 is sufficient for their transcriptional activation. Leveraging lineage barcoding, we show that depleting H3K27me3 alters tumor cell fate under chemotherapy insult - a wider variety of tumor cells tolerate chemotherapy. Our results highlight how chromatin landscapes shape the potential of unchallenged cancer cells to respond to therapeutic stress and pave the way for combinatorial therapy with modulators of chromatin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE186966 | GEO | 2022/02/15

REPOSITORIES: GEO

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H3K27me3 conditions chemotolerance in triple-negative breast cancer [ChIP-reChIP]

Project description:Triple-negative breast cancer is associated with the worst prognosis and the highest risk of recurrence among all breast cancer subtypes1. Residual disease, formed by cancer cells persistent to chemotherapy, remains the major clinical challenge towards full cure2,3. There is now consensus that non-genetic processes contribute to chemoresistance in various tumor types, notably through the initial emergence of a reversible chemotolerant state4–6. Understanding non-genetic tumor evolution stands now as a prerequisite for the design of relevant combinatorial approaches to delay recurrence. Here we show that the repressive histone mark H3K27me3 is a determinant of cell fate under chemotherapy exposure, monitoring epigenomes, transcriptomes and lineage with single-cell resolution. We identify a reservoir of persister basal cells with EMT markers and activated TGF-β pathway leading to multiple chemoresistance phenotypes. We demonstrate that, in unchallenged cells, H3K27 methylation is a lock to the expression program of persister cells. Promoters are primed with both H3K4me3 and H3K27me3, and removing H3K27me3 is sufficient for their transcriptional activation. Leveraging lineage barcoding, we show that depleting H3K27me3 alters tumor cell fate under chemotherapy insult - a wider variety of tumor cells tolerate chemotherapy. Our results highlight how chromatin landscapes shape the potential of unchallenged cancer cells to respond to therapeutic stress and pave the way for combinatorial therapy with modulators of chromatin.

2022-02-15 | GSE186965 | GEO

H3K27me3 conditions chemotolerance in triple-negative breast cancer [scRNA-seq]

2022-02-15 | GSE164715 | GEO

H3K27me3 conditions chemotolerance in triple-negative breast cancer [ChIP-seq]

2022-02-15 | GSE164409 | GEO

H3K27me3 conditions chemotolerance in triple-negative breast cancer [scChIP-seq]

2022-02-15 | GSE164385 | GEO

H3K27me3 conditions chemotolerance in triple-negative breast cancer [WES]

Project description:Triple-negative breast cancer is associated with the worst prognosis and the highest risk of recurrence among all breast cancer subtypes1. Residual disease, formed by cancer cells persistent to chemotherapy, remains the major clinical challenge towards full cure2,3. There is now consensus that non-genetic processes contribute to chemoresistance in various tumor types, notably through the initial emergence of a reversible chemotolerant state4–6. Understanding non-genetic tumor evolution stands now as a prerequisite for the design of relevant combinatorial approaches to delay recurrence. Here we show that the repressive histone mark H3K27me3 is a determinant of cell fate under chemotherapy exposure, monitoring epigenomes, transcriptomes and lineage with single-cell resolution. We identify a reservoir of persister basal cells with EMT markers and activated TGF-? pathway leading to multiple chemoresistance phenotypes. We demonstrate that, in unchallenged cells, H3K27 methylation is a lock to the expression program of persister cells. Promoters are primed with both H3K4me3 and H3K27me3, and removing H3K27me3 is sufficient for their transcriptional activation. Leveraging lineage barcoding, we show that depleting H3K27me3 alters tumor cell fate under chemotherapy insult - a wider variety of tumor cells tolerate chemotherapy. Our results highlight how chromatin landscapes shape the potential of unchallenged cancer cells to respond to therapeutic stress and pave the way for combinatorial therapy with modulators of chromatin

2022-02-16 | GSE196764 | GEO

Single-cell sequencing reveals effects of chemotherapy on the immune landscape and TCR/BCR clonal expansion in a relapsed ovarian cancer patient

Project description:Cancer recurrence and chemoresistance are the leading causes of death in high-grade serous ovarian cancer (HGSOC) patients. However, the unique role of the immune environment in tumor progression for relapsed chemo-resistant patients remains elusive. In single-cell resolution, we characterized a comprehensive multi-dimensional cellular and immunological atlas from tumor, ascites, and peripheral blood of a chemo-resistant patient at different stages of treatment. Our results highlight a role in recurrence and chemoresistance of the immunosuppressive microenvironment in ascites, including MDSC-like myeloid and hypo-metabolic γδT cells, and of peripheral CD8+ effector T cells with chemotherapy-induced senescent/exhaustive. Importantly, paired TCR/BCR sequencing demonstrated relative conservation of TCR clonal expansion in hyper-expanded CD8+ T cells and extensive BCR clonal expansion without usage bias of V(D)J genes after chemotherapy. Thus, our study suggests strategies for ameliorating chemotherapy-induced immune impairment to improve the clinical outcome of HGSOC.

2022-09-15 | GSE213243 | GEO

Fatty acid oxidation protects cancer cells from apoptosis through increasing mitochondrial membrane lipids

Project description:<p>Overcoming resistance to chemotherapies remains a major unmet need for cancers such as triple negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-Oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-CoA. Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.</p>

2022-05-31 | MTBLS4709 | MetaboLights

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]

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.

2022-12-21 | GSE199716 | GEO

TMT-based Quantitative Proteomics Identifies Protein Markers of Resistance to Neoadjuvant Chemotherapy in Ovarian Cancer

Project description:The high rate of recurrence and chemoresistance necessitates in ovarian cancer warrants further research into tumor markers characterizing the resistant population. The proportion of drug-resistant tissue cells in residual lesions after neoadjuvant chemotherapy increases, and drug-resistant markers are enriched. However, there is a lack of comprehensive understanding of tumor marker predoninance pre- and post- neoadjuvant chemotherapy. Here we performed quantitative proteomic analysis of TMT in three patients with matched pretreatment biopsies and post-NACT ovarian cancer tissues. This study highlights a dominant molecular subpopulation that persists in the ovary after neoadjuvant chemotherapy exposure in order to elucidate how it is involved in mediating chemotherapy response, which will lay the foundation for the development.

2023-08-01 | PXD044243 | iProX

PMP22 Regulates Self-Renewal and Chemoresistance of Gastric Cancer Cells

Project description:Cancer stem cells (CSCs) possess self-renewal and chemoresistance activities. However, the manner in which these features are maintained remains obscure. We sought to identify cell surface protein(s) that mark self-renewing and chemoresistant gastric cancer cells using the Explorer Antibody Microarray. We identified PMP22, a target gene of the Wnt/β-catenin pathway, as the most upregulated cell surface protein in gastric cancer xenografts exposed to cisplatin (DDP). PMP22 expression was markedly upregulated in tumorspheric cells and declined with differentiation. Infecting gastric cancer cells with lentivirus expressing PMP22 shRNAs reduced proliferation, tumorsphere formation, and chemoresistance to cisplatin in vitro and in NOD/SCID mice. When combined with bortezomib, a PMP22 inhibitor, the chemotherapeutic sensitivity to cisplatin treatment was dramatically increased by inducing cell apoptosis in cultured cells and xenograft mouse models. Finally, mRNA expression levels of PMP22 were detected in 38 tumor specimens from patients who received 6 cycles of perioperative chemotherapy. A strong correlation between PMP22 level and tumor recurrence was revealed, thus showing a pivotal role of PMP22 in the clinical chemoresistance of gastric cancer. Our study is the first to show the role of PMP22 in gastric cancer stemness and chemoresistance and reveals a potential new target for the diagnosis and treatment of recurrent gastric cancer.

2017-02-10 | GSE94714 | GEO

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