Autophagy promotes Braf V600E -driven lung tumorigenesis by preserving mitochondrial metabolism

• Published in: Autophagy Vol. 10; no. 2; pp. 384 - 385
• Main Authors: Strohecker, Anne M, White, Eileen
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 26.02.2014
• Series: Commentary
• Subjects: Autophagic Punctum
• ISSN: 1554-8627; 1554-8635
• DOI: 10.4161/auto.27320

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.