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To identify novel drivers of PDA malignancy, we employed a regulatory network analysis, which accurately infers the activity of transcription factors and other regulatory proteins based on the integrated expression of their positive and negative target genes. This highly validated approach enables the identification of the most hyper-activated and hyper-repressed regulatory proteins (i.e. the “master regulators (MRs)”) that drive phenotypic distinctions. We applied this technique to a set of 200 laser capture microdissected human PDA samples as well as 45 low-grade precursors for which we had matched histopathological, clinical, and epidemiological annotation. We identified the MRs associated with four malignancy phenotypes: precursors vs. PDA (initiation), low-grade vs. high grade histopathology (progression), survival post resection, and association with KRAS activity. Integrating across these phenotypes, the top MR of PDA malignancy was found to be BMAL2, a member of the PAS family of bHLH transcription factors. Although the canonical function of BMAL2 is linked to the circadian rhythm protein CLOCK, gene set enrichment analysis highlighted a potential role in hypoxia response. We previously demonstrated that PDA in humans and in the genetically engineered “KPC” mouse model is hypovascularized, hypoperfused, and profoundly hypoxic, with a partial oxygen pressure Citation Format: Alvaro Curiel Garcia, Carlo H. Maurer, Kate Hollinshead, Pasquale Laise, Anthony Andren, Stephen A. Sastra, Carmine F. Palermo, Irina R. Sagalovskiy, Li Zhang, Sam Holmstrom, Kristen Johnson, Gulam A. Manji, Alina Luga, Costas A. Lyssiotis, Andrea Califano, Alec Kimmelman, Kenneth P. Olive. BMAL2 is a KRAS-dependent master regulator of hypoxic response in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4803. |
