Autophagy promotes BrafV600E-driven lung tumorigenesis by preserving mitochondrial metabolism

Autophagy
Anne M Strohecker, Eileen White

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...Continue Reading

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Methods Mentioned

BETA
electron microscopy

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