title: Autophagy promotes BrafV600E-driven lung tumorigenesis by preserving mitochondrial metabolism.
abstract: The role of autophagy in cancer is complex and context-dependent. Here we describe work with genetically engineered mouse models of non-small cell lung cancer (NSCLC) in which the tumor-suppressive and tumor-promoting function of autophagy can be visualized in the same system. We discovered that early tumorigenesis in Braf(V600E)-driven lung cancer is accelerated by autophagy ablation due to unmitigated oxidative stress, as observed with loss of Nfe2l2/Nrf2-mediated antioxidant defense. However, this growth advantage is eventually overshadowed by progressive mitochondrial dysfunction and metabolic insufficiency, and is associated with increased survival of mice bearing autophagy-deficient tumors. Atg7 deficiency alters progression of Braf(V600E)-driven tumors from adenomas (Braf(V600E); atg7(-/-)) and adenocarcinomas (trp53(-/-); Braf(V600E); atg7(-/-)) to benign oncocytomas that accumulated morphologically and functionally defective mitochondria, suggesting that defects in mitochondrial metabolism may compromise continued tumor growth. Analysis of tumor-derived cell lines (TDCLs) revealed that Atg7-deficient cells are significantly more sensitive to starvation than Atg7-wild-type counterparts, and are impaired in their ability to respire, phenotypes that are rescued by the addition of exogenous glutamine. Taken together, these data suggest that Braf(V600E)-driven tumors become addicted to autophagy as a means to preserve mitochondrial function and glutamine metabolism, and that inhibiting autophagy may be a powerful strategy for Braf(V600E)-driven malignancies.
authors.affiliation: Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA; Department of Molecular Biology and Biochemistry; Rutgers University; Piscataway, NJ USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Strohecker
authors.affiliation: Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA; Department of Molecular Biology and Biochemistry; Rutgers University; Piscataway, NJ USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: White
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: Braf; NSCLC; autophagy; glutamine; metabolism; oncocytoma