Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species
J Manent, S Banerjee, R de Matos Simoes, T Zoranovic, C Mitsiades, JM Penninger, KJ Simpson, PO Humbert, HE Richardson
ONCOGENE | NATURE PUBLISHING GROUP | Published : 2017
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..View full abstract
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Awarded by National Health and Medical Research Council (NHMRC)
Awarded by NHMRC
We thank Donna Denton, Sharad Kumar, Louise Cheng, Tor Erik Rusten, Lee Jun, Gabor Juhasz, Tom Neufeld, Stephen Gregory and Zeeshan Shaukat for reagents, and Tor Erik Rusten, Andreas Bergmann, Donna Denton, Sharad Kumar and Stephen Gregory for discussions. We thank Edwina McGlinn for critical reading of the manuscript. We are grateful to the Peter MacCallum Microscopy core and the LIMS Bioimaging facility for their help with imaging and analysis. We are grateful to OzDros and to Peter Burke for quarantine, shipment and maintenance of Drosophila stocks. The project was supported by grants from the National Health and Medical Research Council (NHMRC, no. 1020525) and from the PeterMac Foundation to HER, JMP, KJS and POH, and funds from LIMS and La Trobe University. JM was supported by an NHMRC grant (no. 1020525) and LIMS and La Trobe University, SB by a Australian Postgraduate Research Award and TZ by a Marie Curie Excellence grant. HER and POH are supported by fellowships of the (NHMRC) and funds from LIMS and La Trobe University.