Oncogenic KRAS induces NIX-mediated mitophagy to promote pancreatic cancer

Timothy 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 H. Vousden, David A. Tuveson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1268-1287
Number of pages20
JournalCancer Discovery
Volume9
Issue number9
Early online date1 Jul 2019
DOIs
Publication statusPublished - 1 Sep 2019
Externally publishedYes

Keywords

  • cancer
  • pancreatic cancer
  • mitochondria

ASJC Scopus subject areas

  • Oncology

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