Ras-dependent activation of BMAL2 regulates hypoxic metabolism in pancreatic cancer.

There is a surprising disconnect between the genomic alterations present in pancreatic ductal adenocarcinoma and key phenotypes of malignancy, suggesting that non-genetic factors must play a role. Here we analyze changes in regulatory state - calculated from network analysis of RNA expression data - to identify transcription factors and other regulatory proteins whose activities drive pancreatic cancer malignancy. We identified the top candidate, BMAL2, as a novel, KRAS-responsive regulator of hypoxic response in pancreatic cancer, serving as a switch between HIF1A and HIF2A expression. These data help explain how KRAS coordinates cell regulatory state to enable tumor cells to survive extreme hypoxia, and highlight the ability of regulatory network analysis to identify overlooked, key drivers of biological phenotypes.