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
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > neoplasms
organism description > animal
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > KRAS
organism description > animal > mammal
organs, tissues, organelles, cell types and functions > organelles, types and functions > mitochondria
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogenes
organs, tissues, organelles, cell types and functions > organelles, types and functions
organs, tissues, organelles, cell types and functions
diseases & disorders > cancer > cancer types > pancreatic cancer
organism description > animal > mammal > rodent
CSHL Authors:
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: 02 Feb 2024 15:54
PMCID: PMC6726540
Related URLs:
URI: https://repository.cshl.edu/id/eprint/38147

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