Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis
Open accessAbstract
Macroautophagy (autophagy hereafter) degrades and recycles proteins and organelles to support metabolism and survival in starvation. Oncogenic Ras up-regulates autophagy, and Ras-transformed cell lines require autophagy for mitochondrial function, stress survival, and engrafted tumor growth. Here, the essential autophagy gene autophagy-related-7 ( atg7 ) was deleted concurrently with K-ras G12D activation in mouse models for non-small-cell lung cancer (NSCLC). atg7 -deficient tumors accumulated dysfunctional mitochondria and prematurely induced p53 and proliferative arrest, which reduced tumor burden that was partly relieved by p53 deletion. atg7 loss altered tumor fate from adenomas and carcinomas to oncocytomas—rare, predominantly benign tumors characterized by the accumulation of defective mitochondria. Surprisingly, lipid accumulation occurred in atg7 -deficient tumors only when p53 was deleted. atg7 - and p53 -deficient tumor-derived cell lines (TDCLs) had compromised starvation survival and formed lipidic cysts instead of tumors, suggesting defective utilization of lipid stores. atg7 deficiency reduced fatty acid oxidation (FAO) and increased sensitivity to FAO inhibition, indicating that with p53 loss, Ras-driven tumors require autophagy for mitochondrial function and lipid catabolism. Thus, autophagy is required for carcinoma fate, and autophagy defects may be a molecular basis for the occurrence of oncocytomas. Moreover, cancers require autophagy for distinct roles in metabolism that are oncogene- and tumor suppressor gene-specific.
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Autophagy deficiency suppresses KrasG12D-driven lung cancer development even without Trp53, presumably partly due to mitochondrial dysfunction.
“in contrast to the pancreas model, autophagy deficiency (by autophagy related 7 (Atg7) knockout) suppresses Kras G12D -driven lung cancer development even in the absence of Trp53; presumably this is partially due to mitochondrial dysfunction.”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [88]
In KrasG12V-driven lung tumorigenesis, autophagy deficiency diverts adenoma or adenocarcinoma into oncocytoma regardless of p53 status.
“In the lung model, regardless of p53 status, autophagy deficiency diverts adenoma or adenocarcinoma into oncocytoma, a rare and predominantly benign tumour characterised by the accumulation of respiration-defective mitochondria 88 .”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [88]
Inhibition of autophagy may accelerate organismal decay.
“but may accelerate organismal decay (Guo et al, 2013; Yang et al, 2020)”
From Autophagy in major human diseases (2021) · cites this paper as Guo et al, 2013
Deletion of Atg7 changes lung tumors driven by KrasG12D and BrafV600E from malignant adenocarcinomas to benign oncocytomas.
“deletion of a core component of the autophagy machinery, Atg7, was shown to dramatically change the nature of lung tumors driven by KrasG12D and BrafV600E oncogenes from malignant adenocarcinomas to benign oncocytomas”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Guo et al., 2013
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Background
- Authors
- Guo, J. Y., Karsli-Uzunbas, G., Mathew, R., Aisner, S. C., Kamphorst, J. J., Strohecker, A. M., Chen, G., Price, S., Lu, W., Teng, X., Snyder, E., Santanam, U., DiPaola, R. S., Jacks, T., Rabinowitz, J. D., & White, E.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Rutgers Cancer Institute (US)
- Princeton University (US)
- Brigham and Women's Hospital (US)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2013-07-01
- Volume
- 27
- Issue
- 13
- Pages
- 1447-1461
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3713426
- OpenAlex
- W2127377435
- Cited by
- 589
- References
- 34
- Citations by year
- 2026: 16 · 2025: 23 · 2024: 26 · 2023: 33 · 2022: 45 · 2021: 56 · 2020: 61 · 2019: 54 · 2018: 55 · 2017: 42 · 2016: 62 · 2015: 54 · 2014: 50 · 2013: 10
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- U.S. Department of Defense (W81XWH)
- Rutgers Cancer Institute of New Jersey
- Hope Funds for Cancer Research
- National Institutes of Health (W81XWH, R37 CA53370)
- National Cancer Institute (R37CA053370, R37-CA53370, RC1CA147961, R01CA130893)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- autophagy, KRAS G12D, oncocytoma, non-small cell lung cancer, ATG7, p53, mitochondrial dysfunction, lipid homeostasis, fatty acid oxidation, tumor progression, lipid accumulation, tumor-derived cell lines, cancer metabolism
- MeSH terms
- Animals, Autophagy, Carcinoma, Non-Small-Cell Lung, Homeostasis, Longevity, Lung Neoplasms, Mitochondria, Genes, ras, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Genes, p53, Gene Deletion, Adenoma, Oxyphilic, Cell Line, Tumor, Lipid Metabolism, Mice
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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