Abstract

Pancreatic cancer is a leading cause of mortality worldwide due to difficulty detecting early-stage disease and our poor understanding of the mediators that drive the progression of hypoxic solid tumours. We, therefore, used a heavy isotope pulse/trace proteomic approach to determine how hypoxia alters pancreatic tumour expression of proteins that confer treatment resistance, promote metastasis, and suppress host immunity. Using this method, we identified that hypoxia stress stimulates pancreatic cancer cells to rapidly translate proteins that enhance metastasis (NOTCH2, NCS1, CD151, NUSAP1), treatment resistant (ABCB6), immune suppression (NFIL3,WDR4), angiogenesis (ANGPT4, ERO1, FOS), alter cell metabolic activity (HK2, ENO2), and mediate growth-promoting cytokine responses (CLK3, ANGPTL4). Database mining confirmed that elevated gene expression of these hypoxia-induced mediators is significantly associated with poor patient survival in various stages of pancreatic cancer. Among these proteins, the oxidoreductase enzyme ERO1 was highly sensitive to induction by hypoxia stress across a range of different pancreatic cancer cell lines and was associated with particularly poor prognosis in human patients. Consistent with these data, genetic deletion of ERO1 substantially reduced growth rates and colony formation in pancreatic cancer cells when assessed in a series of functional assays in vitro. Accordingly, when transferred into a mouse xenograft model, ERO1-deficient tumour cells exhibited severe growth restriction and negligible disease progression in vivo. Together, these data indicate that ERO1 is potential prognostic biomarker and novel drug target for pancreatic cancer therapy.