Identification of hypoxia-induced proteins using SILAC-based proteomics

A hallmark of solid tumours is the development of hypoxic regions where rapidly growing transformed cells outstrip their blood supply. Tumour cells in these starved regions sense reduced levels of oxygen and switch on genes that help them to adapt, survive and continue growing. Since hypoxia is a key physiological difference between normal and cancer tissue, an opportunity exists to selectively kill tumour cells by exploiting the differences in protein expression between normal and hypoxic tumour tissue. However, a major challenge is to identify druggable hypoxia-induced proteins critical for tumour cell survival. This is especially important in cancers of unmet need where hypoxia gene signatures correlate with poor prognosis (for example, colorectal cancers). To identify new hypoxia-induced proteins, we performed SILAC-based proteomics on colorectal cancer cells exposed to normoxia and hypoxia. In this study, we identify a new hypoxia-activated GPCR signalling axis that enables colorectal tumour cells to survive the microenvironmental stress of hypoxia. Our findings uncover a previously unappreciated role for this GPCR-axis as a key regulator of the adaptive response to hypoxia and highlght an opportunity to exploit tumour-associated hypoxia for therapy.