Abstract NG04: BMAL2 is a KRAS-driven master regulator of hypoxic adaptation and EMT in pancreatic ductal adenocarcinoma
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human malignancies, with a five-year survival rate below 15%. In contrast to several other solid tumors where chemotherapy, radiotherapy, and immune checkpoint blockade have significantly improved outcomes, PDAC remains largely refractory to current therapeutic strategies. One hallmark of PDAC is its profoundly hypoxic tumor microenvironment. Extensive desmoplasia and limited vascularization restrict oxygen delivery to tumor tissues, creating regions of severe oxygen deprivation. KRAS, the primary oncogenic driver of PDAC, can activate transcriptional programs that rewire cellular metabolism and enable tumor cell survival under oxygen limitation. However, the precise molecular mechanisms connecting oncogenic KRAS signaling to hypoxia-adaptive transcriptional programs remain poorly defined. To identify the top transcriptional regulators associated with KRAS, we integrated clinical and pathological information with gene expression data derived from laser captured, microdissected human PDAC epithelium. Across 242 transcriptional profiles, including 197 PDAC tumors and 45 benign precursor lesions, regulatory network analysis identified BMAL2, a member of the PAS superfamily typically associated with the regulation of circadian rhythms, as the top KRAS-associated transcriptional regulator and one of the strongest drivers of tumor initiation, progression, and post-resection survival. We found that BMAL2 activity…
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