Oncogenic Kras induces Nix-mediated mitophagy to promote pancreatic cancer

Humpton, T. J., Alagesan, B., DeNicola, G. M., Lu, D., Yordanov, G. N., Leonhardt, C. S., Yao, M. A., Alagesan, P., Zaatari, M. N., Park, Y., Skepper, J. N., Macleod, K. F., Perez-Mancera, P. A., Murphy, M. P., Evan, G. I., Vousden, K. H., Tuveson, D. A. (July 2019) Oncogenic Kras induces Nix-mediated mitophagy to promote pancreatic cancer. Cancer Discov, 99 (9). pp. 1268-1298. ISSN 2159-8274

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. 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.

Item Type:	Paper
Subjects:	bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > KRAS organs, tissues, organelles, cell types and functions > organelles, types and functions > mitochondria diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:	Tuveson, David A. Park, Youngkyu Alagesan, Brinda Yordanov, Georgi Yao, Melissa Alageson, Priya Leonhardt, Carl S. Zaatari, Maya N.
Communities:	CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Shared Resources > Animal Shared Resource CSHL labs > Tuveson lab School of Biological Sciences > Publications
Depositing User:	Matthew Dunn
Date:	1 July 2019
Date Deposited:	05 Aug 2019 15:57
Last Modified:	09 Sep 2021 18:26
PMCID:	PMC6726540
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/38147

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