| First Author | Strohecker AM | Year | 2014 |
| Journal | Autophagy | Volume | 10 |
| Issue | 2 | Pages | 384-5 |
| PubMed ID | 24362353 | Mgi Jnum | J:320510 |
| Mgi Id | MGI:6872911 | Doi | 10.4161/auto.27320 |
| Citation | Strohecker AM, et al. (2014) Autophagy promotes BrafV600E-driven lung tumorigenesis by preserving mitochondrial metabolism. Autophagy 10(2):384-5 |
| abstractText | 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. |
