HIF2α cooperates with RAS to promote lung tumorigenesis in mice

Members of the hypoxia-inducible factor (HIF) family of transcription factors regulate the cellular response to hypoxia. In non-small cell lung cancer (NSCLC), high HIF2 alpha levels correlate with decreased overall survival, and inhibition of either the protein encoded by the canonical HIF target gene VEGF or VEGFR2 improves clinical outcomes. However, whether HIF2 alpha is causal in imparting this poor prognosis is unknown. Here, we generated mice that conditionally express both a nondegradable variant of HIF2 alpha and a mutant form of Kras (Kras(G12)) that induces lung tumors. Mice expressing both Hij2 alpha and Kras(G12D) in the lungs developed larger tumors and had an increased tumor burden and decreased survival compared with mice expressing only Kras(G12D). Additionally, tumors expressing both Kras(G12D) and Hij2 alpha were more invasive, demonstrated features of epithelial-mesenchymal transition (EMT), and exhibited increased angiogenesis associated with mobilization of circulating endothelial progenitor cells. These results implicate HIF2 alpha causally in the pathogenesis of lung cancer in mice, demonstrate in vivo that HIF2 alpha can promote expression of markers of EMT, and define HIF2 alpha as a promoter of tumor growth and progression in a solid tumor other than renal cell carcinoma. They further suggest a possible causal relationship between HIF2 alpha and prognosis in patients with NSCLC.