title: Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila.
abstract: Mitochondrial respiratory function is frequently impaired in human cancers. 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.
authors.affiliation: Division of Genetics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Shizue
authors.initials: S
authors.lastname: Ohsawa
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sato
authors.forename: Masato
authors.initials: M
authors.lastname: Enomoto
authors.forename: Mai
authors.initials: M
authors.lastname: Nakamura
authors.forename: Aya
authors.initials: A
authors.lastname: Betsumiya
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Igaki
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D054910:Compound Eye, Arthropod / Q000254:growth & development / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D018450:Disease Progression; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D060227:Imaginal Discs / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D051155:Wnt1 Protein / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D015689:Oncogene Protein p21(ras); D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D051155:Wnt1 Protein; C115570:upd1 protein, Drosophila; C074622:wg protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases