Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species

Oncogene. 2017 Oct 5;36(40):5576-5592. doi: 10.1038/onc.2017.175. Epub 2017 Jun 5.


Activation of Ras signalling occurs in ~30% of human cancers; however, activated Ras alone is not sufficient for tumourigenesis. In a screen for tumour suppressors that cooperate with oncogenic Ras (RasV12) in Drosophila, we identified genes involved in the autophagy pathway. Bioinformatic analysis of human tumours revealed that several core autophagy genes, including GABARAP, correlate with oncogenic KRAS mutations and poor prognosis in human pancreatic cancer, supporting a potential tumour-suppressive effect of the pathway in Ras-driven human cancers. In Drosophila, we demonstrate that blocking autophagy at any step of the pathway enhances RasV12-driven epithelial tissue overgrowth via the accumulation of reactive oxygen species and activation of the Jun kinase stress response pathway. Blocking autophagy in RasV12 clones also results in non-cell-autonomous effects with autophagy, cell proliferation and caspase activation induced in adjacent wild-type cells. Our study has implications for understanding the interplay between perturbations in Ras signalling and autophagy in tumourigenesis, which might inform the development of novel therapeutics targeting Ras-driven cancers.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis Regulatory Proteins
  • Autophagy* / genetics
  • Carcinogenesis* / genetics
  • Cell Transformation, Neoplastic
  • Drosophila melanogaster
  • Female
  • Gene Knockdown Techniques
  • Genes, ras*
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Microtubule-Associated Proteins / metabolism
  • Oxidative Stress
  • Reactive Oxygen Species / metabolism*
  • Survival Analysis
  • Vesicle-Associated Membrane Protein 2 / metabolism


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • GABARAP protein, human
  • Microtubule-Associated Proteins
  • Reactive Oxygen Species
  • VAMP2 protein, human
  • Vesicle-Associated Membrane Protein 2