Overall, our integrative analyses of multiple genomics data sets, together with data from over 600 cancer cell lines and 11,000 human tumor samples, indicate that HIF1A is the main driver of the acute transcriptional response to hypoxia, and that this transcriptional program encodes divergent functions linked to intrinsic suppression of cancer cell proliferation as well as cell-extrinsic disease progression via ECM remodeling. Here, HIF1A is linked to neoplasm.