Oncogenic KRAS induces NIX-mediated mitophagy to promote pancreatic cancer
Open accessPublished version of a preprint
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. This article is highlighted in the In This Issue feature, p. 1143
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Genetic inhibition of critical autophagy proteins in mice leads to regression of autochthonous PDAC tumors.
“genetic inhibition of critical autophagy proteins in mice leads to regression of autochthonous PDAC tumors210”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [210]
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- Authors
- 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.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- Cold Spring Harbor Laboratory (US)
- Moffitt Cancer Center (US)
- 6Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
- University of Cambridge (GB)
- University of Chicago (US)
- 9Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
- The Francis Crick Institute (GB)
- Corresponding author
- Tuveson, David A.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2019-09-01
- Volume
- 9
- Issue
- 9
- Pages
- 1268-1287
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6726540
- OpenAlex
- W2955374764
- Cited by
- 198
- References
- 65
- Citations by year
- 2026: 24 · 2025: 28 · 2024: 28 · 2023: 32 · 2022: 31 · 2021: 24 · 2020: 25 · 2019: 5
- FWCI
- 16.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Cold Spring Harbor Laboratory Association
- V Foundation
- Cold Spring Harbor Laboratory (P30 CA196521)
- Northwell Health Affiliation (4K00CA212455-03)
- NIH (5P30CA45508, 5P50CA101955, P20CA192996, 1U10CA180944, U01CA224013, U01CA210240-01A1, 1R01CA188134, 1R01CA190092)
- NCI (5F30CA200240, R50CA211506)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- oncogenic KRAS, Nix, BNIP3L, mitophagy, pancreatic ductal adenocarcinoma, pancreatic intraepithelial neoplasia, mitochondrial clearance, glycolysis, redox homeostasis, NADPH, glucose flux, tumor progression, KPC mouse model
- MeSH terms
- Animals, Glycolysis, Humans, Membrane Proteins, Mitochondria, Mutation, NADP, Neoplasm Transplantation, Oxidation-Reduction, Pancreatic Neoplasms, Proto-Oncogene Proteins, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Carcinoma, Pancreatic Ductal, Tumor Suppressor Proteins, Cell Line, Tumor, Mice, Mitophagy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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