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

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.