Oncogenic KRAS induces NIX-mediated mitophagy to promote pancreatic cancer
Authors listTimothy J Humpton Brinda Alagesan Gina M DeNicola Dan Lu Georgi N Yordanov Carl S Leonhardt Melissa A Yao Priya Alagesan Maya N Zaatari Youngkyu Park Jeremy N Skepper Kay F Macleod Pedro A Perez-Mancera Michael P Murphy Gerard I Evan Karen Vousden David A Tuveson
Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic KRAS induces BNIP3L/NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. While conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and PanIN lesions progress to PDAC. We identify the Kras-Nix mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC.
Journal Cancer Discovery
Issue number 9