Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer.
Humpton, Timothy J
DeNicola, Gina M
Yordanov, Georgi N
Leonhardt, Carl S
Yao, Melissa A
Zaatari, Maya N
Skepper, Jeremy N
Macleod, Kay F
Perez-Mancera, Pedro A
Vousden, Karen H
Tuveson, David A
American Association for Cancer Research Inc.
MetadataShow full item record
Humpton, T. J., Alagesan, B., DeNicola, G. M., Lu, D., Yordanov, G. N., Leonhardt, C. S., Yao, M. A., et al. (2019). Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer.. Cancer Discovery, 9 (9), 1268-1287. https://doi.org/10.1158/2159-8290.CD-18-1409
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. Although conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and pancreatic intraepithelial neoplasia (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. SIGNIFICANCE: NIX-mediated mitophagy is a new oncogenic KRAS effector pathway that suppresses functional mitochondrial content to stimulate cell proliferation and augment redox homeostasis. This pathway promotes the progression of PanIN to PDAC and represents a new dependency in pancreatic cancer.This article is highlighted in the In This Issue feature, p. 1143.
Includes: M.P. Murphy is supported by Medical Research Council UK (MC_UU_00015/3) and by a Wellcome Trust Investigator award (110159/Z/15/Z). T.J. Humpton and K.H. Vousden are supported by Cancer Research UK and by ERC grant 322842-METABOp53. T.J. Humpton was also supported by the Gates Cambridge Trust. G.I. Evan and D. Lu are supported by Cancer Research UK Programme Grant A12077 (principal investigator: G.I. Evan):
Wellcome Trust (110159/Z/15/Z)
External DOI: https://doi.org/10.1158/2159-8290.CD-18-1409
This record's URL: https://www.repository.cam.ac.uk/handle/1810/298187
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