Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis

Jessie Yanxiang Guo, Gizem Karsli-Uzunbas, Robin Mathew, Seena C. Aisner, Jurre J. Kamphorst, Anne M. Strohecker, Guanghua Chen, Sandy Price, Wenyun Lu, Xin Teng, Eric Snyder, Urmila Santanam, Robert S. DiPaola, Tyler Jacks, Joshua D. Rabinowitz, Eileen White

Research output: Contribution to journalArticle

317 Scopus citations

Abstract

Macroautolcell (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-rasG12D 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.

Original languageEnglish (US)
Pages (from-to)1447-1461
Number of pages15
JournalGenes and Development
Volume27
Issue number13
DOIs
StatePublished - Jul 1 2013

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Keywords

  • Autophagy
  • Fatty acid oxidation
  • K-ras
  • Metabolism
  • Mitochondria
  • NSCLC
  • Oncocytoma
  • P53

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  • Cite this

    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. (2013). Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes and Development, 27(13), 1447-1461. https://doi.org/10.1101/gad.219642.113