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The chromatin landscape of high-grade serous ovarian cancer metastasis identifies potential regulatory drivers of chemoresistant tumour cells

ABSTRACT: Disease recurrence following chemotherapy is a major clinical challenge in ovarian cancer (OC) but little is known regarding how the tumour epigenome regulates transcriptional programs underpinning chemoresistance. We determined the single cell chromatin accessibility landscape of omental OC metastasis from treatment naïve and neoadjuvant chemotherapy-treated patients and defined the chromatin accessibility profiles of epithelial, fibroblast, myeloid and lymphoid cells. Epithelial tumour cells displayed open chromatin regions enriched with motifs for the oncogenic transcription factors MEIS and PBX. Chemotherapy drove profound tumour heterogeneity and selection for cells with accessible chromatin enriched for TP53, TP63 and resistance-pathway-activating TF motifs. Nuclear receptors RORa, NR2F6 and HNF4NG were identified as candidate transcriptional drivers of stress-associated chemotherapy resistance whilst closure of binding sites for E2F2 and E2F4 indicated low proliferative capacity of resistant tumour subsets. Delineation of the epigenetic landscape of chemoresistant ovarian cancer therefore reveals core transcriptional regulators of chemoresistance and identifies potential novel therapeutic approaches for improving clinical outcome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247982 | GEO | 2024/10/02

REPOSITORIES: GEO

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Project description:Multiple DNA methylation changes have been associated with the acquisition of drug resistance; however it remains uncertain how many of these changes may represent critical DNA methylation drivers of chemoresistance. Using genome-wide DNA methylation profiling across 27,578 CpG sites on Illumina HumanMethylation27 bead array we identified loci at 4092 genes becoming hypermethylated in the chemoresistant A2780/cp70 ovarian tumour cell line compared to the parental sensitive A2780 line. Hypermethylation at CpG islands (CGI) is often associated with transcriptional silencing, however only 245 of these hypermethylated genes become down-regulated in A2780/cp70 as measured by microarray expression profiling. Treatment with the demethylating agent Decitabine induces re-sensitisation to cisplatin and resulted in re-expression of 41 of the down-regulated genes in cisplatin-resistant cells at the time point when re-sensitisation occurs. 13 of the 41 genes were consistently hypermethylated in two further independent cisplatin-resistant A2780 cell derivatives. Nine out of the 13 genes (ARHGDIB, ARMCX2, COL1A, FLNA, FLNC, MEST, MLH1, NTS, PSMB9) acquired methylation at CpG sites in ovarian tumours at relapse following chemotherapy or chemoresistant cell lines derived at the time of patient relapse. Furthermore, 5/13 candidate genes acquired methylation in drug-resistant in vivo-derived ovarian cancer sustaining (side population) cells. Therefore, this small set of genes are potential key drivers of chemoresistance and should be further evaluated as predictive biomarkers, both to existing chemotherapies, but also to epigenetic therapies used to modulate drug resistance. Array-based methylation profiling was performed using the Infinium HumanMethylation27 BeadChip in two cisplatin sensitive cell lines and three cisplatin resistant cell lines derived in vitro, four pairs of cisplatin sensitive and resistant cell lines derived in vivo, 7 pairs of tumour tissues obtained from patients before chemotherapy and at disease relapse, 2 pairs of IGROV1 SP and NSP cells. The reproducibility of the Infinium HumanMethylation27 BeadChips was evaluated using biological and technical replicates of matched chemosensitive/chemoresistant ovarian cancer cell lines PEO1/PEO4. Differential methylation cutoff was estimated from two biological replicates by bootstrap resampling.

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The chromatin landscape of high-grade serous ovarian cancer metastasis identifies potential regulatory drivers of chemoresistant tumour cells

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