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, J. M. Penninger, K. J. Simpson, P. O. Humbert, H. E. Richardson

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Abstract

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 (Ras V12) 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 Ras V12-driven epithelial tissue overgrowth via the accumulation of reactive oxygen species and activation of the Jun kinase stress response pathway. Blocking autophagy in Ras V12 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.

Original languageEnglish
Pages (from-to)5576-5592
Number of pages17
JournalOncogene
Volume36
Issue number40
DOIs
Publication statusPublished - 5 Oct 2017

Cite this

Manent, J., Banerjee, S., De Matos Simoes, R., Zoranovic, T., Mitsiades, C., Penninger, J. M., ... Richardson, H. E. (2017). Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species. Oncogene, 36(40), 5576-5592. https://doi.org/10.1038/onc.2017.175
Manent, J. ; Banerjee, S. ; De Matos Simoes, R. ; Zoranovic, T. ; Mitsiades, C. ; Penninger, J. M. ; Simpson, K. J. ; Humbert, P. O. ; Richardson, H. E. / Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species. In: Oncogene. 2017 ; Vol. 36, No. 40. pp. 5576-5592.
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abstract = "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 (Ras V12) 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 Ras V12-driven epithelial tissue overgrowth via the accumulation of reactive oxygen species and activation of the Jun kinase stress response pathway. Blocking autophagy in Ras V12 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.",
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Manent, J, Banerjee, S, De Matos Simoes, R, Zoranovic, T, Mitsiades, C, Penninger, JM, Simpson, KJ, Humbert, PO & Richardson, HE 2017, 'Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species', Oncogene, vol. 36, no. 40, pp. 5576-5592. https://doi.org/10.1038/onc.2017.175

Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species. / Manent, J.; Banerjee, S.; De Matos Simoes, R.; Zoranovic, T.; Mitsiades, C.; Penninger, J. M.; Simpson, K. J.; Humbert, P. O.; Richardson, H. E.

In: Oncogene, Vol. 36, No. 40, 05.10.2017, p. 5576-5592.

Research output: Contribution to journalArticleResearchpeer-review

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Manent J, Banerjee S, De Matos Simoes R, Zoranovic T, Mitsiades C, Penninger JM et al. Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species. Oncogene. 2017 Oct 5;36(40):5576-5592. https://doi.org/10.1038/onc.2017.175