Hypoxia drives ERO1A-dependent angiogenesis in ovarian cancer cells promotes peritoneal metastasis and platinum resistance

Abstract

High-grade serous ovarian cancer (HGSOC) is characterized by early peritoneal dissemination and frequent platinum resistance, yet the epithelial states and mechanisms that couple metastasis, angiogenesis, and therapy response remain incompletely defined. We integrated in-house single-cell RNA sequencing of 82,149 cells from 21 treatment-naïve HGSOC specimens with external spatial transcriptomic and single-cell datasets to identify metastasis-associated epithelial programs. A hypoxia-enriched epithelial subcluster (E04) was preferentially expanded in advanced and metastatic lesions, showed high copy-number burden, and was defined by strong ERO1A expression. Spatial analyses and multiplex immunofluorescence showed that ERO1A-positive tumor cells were preferentially associated with endothelial niches and VEGFA-rich regions. Mechanistically, hypoxia induced ERO1A in a HIF1α-dependent manner, whereas ERO1A promoted VEGFA secretion mainly by facilitating disulfide bond-related oxidative maturation rather than by markedly increasing VEGFA transcription or total protein abundance. Functionally, ERO1A enhanced migration, invasion, angiogenesis, and cisplatin resistance in ovarian cancer cells. Clinically, high ERO1A expression was associated with shorter platinum-free interval. In orthotopic models, intraperitoneal cisplatin plus the ERO1A inhibitor EN460 produced stronger antitumor effects than either monotherapy, and VEGFA knockdown largely abrogated this additional in vivo benefit, indicating that VEGFA-dependent angiogenesis is required for the full efficacy of the combination. These findings identify a conserved hypoxia-HIF1α-ERO1A-VEGFA axis that links pro-angiogenic secretion to peritoneal metastasis and platinum resistance, and support ERO1A inhibition plus platinum as a rational therapeutic strategy in advanced HGSOC.