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Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila

Nature volume 490, pages 547–551 (2012)Cite this article

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Abstract

Mitochondrial respiratory function is frequently impaired in human cancers1,2,3,4. However, the mechanisms by which mitochondrial dysfunction contributes to tumour progression remain elusive. Here we show in Drosophila imaginal epithelium that defects in mitochondrial function potently induce tumour progression of surrounding tissue in conjunction with oncogenic Ras. Our data show that Ras activation and mitochondrial dysfunction cooperatively stimulate production of reactive oxygen species, which causes activation of c-Jun amino (N)-terminal kinase (JNK) signalling. JNK cooperates with oncogenic Ras to inactivate the Hippo pathway, leading to upregulation of its targets Unpaired (an interleukin-6 homologue) and Wingless (a Wnt homologue). Mitochondrial dysfunction in Ras-activated cells further cooperates with Ras signalling in neighbouring cells with normal mitochondrial function, causing benign tumours to exhibit metastatic behaviour. Our findings provide a mechanistic basis for interclonal tumour progression driven by mitochondrial dysfunction and oncogenic Ras.

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Figure 1: RasV12/mito−/− clones cause non-autonomous overgrowth through JNK-mediated Upd induction.
Figure 2: JNK signalling is activated by oxidative stress in RasV12/mito−/− clones.
Figure 3: Co-activation of JNK and Ras signalling causes upregulation of Upd and Wg through Hippo pathway inactivation.
Figure 4: RasV12/mito−/− clones drive tumour progression of surrounding tumours.

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Acknowledgements

We thank J. Pastor-Pareja and M. Miura for comments on the manuscript; T. Sawada and K. Takino for technical support; D. Harrison, T. Orr-Weaver and H. Richardson for antibodies; T. Adachi-Yamada, U. Banerjee, D. Bohmann, F. Missirlis, M. Miura, H. Sun, T. Xu, Y. Hiromi, the Bloomington Stock Center, the Vienna Drosophila RNAi Center, the National Institute of Genetics Stock Center and the Drosophila Genetic Resource Center for fly stocks. We also thank T. Xu for encouragement. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to S.O., M.E. and T.I, a Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT to S.O. and T.I., the Japan Society for the Promotion of Science for Young Scientists to S.O. and M.E., the Japan Science and Technology Agency to T.I., the G-COE program for Global Center for Education and Research in Integrative Membrane Biology to S.O. and T.I.,the Fumi Yamamura Memorial Foundation for Female Natural Scientists to S.O, the Tomizawa Jun-ichi & Keiko Fund of the Molecular Biology Society of Japan for Young Scientists to S.O., the Takeda Science Foundation to S.O. and T.I., the Astellas Foundation for Research on Metabolic Disorders to T.I., the Kanae Foundation for the Promotion of Medical Science to T.I., the Senri Life Science Foundation to T.I. and a Human Frontier Science Program Career Development Award to T.I.

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Authors and Affiliations

  1. Division of Genetics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan,

    Shizue Ohsawa, Yoshitaka Sato, Masato Enomoto, Mai Nakamura, Aya Betsumiya & Tatsushi Igaki

  2. PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan,

    Tatsushi Igaki

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  1. Shizue Ohsawa
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Contributions

S.O., Y.S., M.E. and T.I. designed the research, S.O., Y.S., M.E., M.N., A.B. and T.I. performed experiments, S.O., Y.S., M.E. and T.I. analysed the data, and S.O. and T.I. wrote the manuscript.

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Correspondence to Tatsushi Igaki.

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The authors declare no competing financial interests.

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Ohsawa, S., Sato, Y., Enomoto, M. et al. Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila. Nature 490, 547–551 (2012). https://doi.org/10.1038/nature11452

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