Cell Competition Drives the Growth of Intestinal Adenomas in Drosophila.

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Suijkerbuijk, Saskia JE 

Tumor-host interactions play an increasingly recognized role in modulating tumor growth. Thus, understanding the nature and impact of this complex bidirectional communication is key to identifying successful anti-cancer strategies. It has been proposed that tumor cells compete with and kill neighboring host tissue to clear space that they can expand into; however, this has not been demonstrated experimentally. Here we use the adult fly intestine to investigate the existence and characterize the role of competitive tumor-host interactions. We show that APC(-/-)-driven intestinal adenomas compete with and kill surrounding cells, causing host tissue attrition. Importantly, we demonstrate that preventing cell competition, by expressing apoptosis inhibitors, restores host tissue growth and contains adenoma expansion, indicating that cell competition is essential for tumor growth. We further show that JNK signaling is activated inside the tumor and in nearby tissue and is required for both tumor growth and cell competition. Lastly, we find that APC(-/-) cells display higher Yorkie (YAP) activity than host cells and that this promotes tumor growth, in part via cell competition. Crucially, we find that relative, rather than absolute, Hippo activity determines adenoma growth. Overall, our data indicate that the intrinsic over-proliferative capacity of APC(-/-) cells is not uncontrolled and can be constrained by host tissues if cell competition is inhibited, suggesting novel possible therapeutic approaches.

Drosophila, Hippo signaling, JNK signaling, Yki/YAP/TAZ, adenomatous polyposis coli (APC), apoptosis, cancer, cell competition, cell death, intestinal adenomas, posterior midgut, tumor microenvironment, Adenoma, Animals, Carcinogenesis, Cell Proliferation, Cell Transformation, Neoplastic, Disease Models, Animal, Drosophila melanogaster, Humans, Intestinal Neoplasms, Signal Transduction
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Curr Biol
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Elsevier BV
Cancer Research Uk (None)
The Royal Society (uf140713)
Wellcome Trust (092096/Z/10/Z)
Netherlands Organisation for Scientific Research (NWO) (File No: 82512027)
Cancer Research Uk (None)
This work was supported by a Cancer Research UK Programme Grant (EP and GK A12460), a Royal Society University Research fellowship to EP (UF0905080), an EMBO Long-Term Fellowship (ALTF 1476-2012), a NWO Rubicon grant (825.12.027) and a Dutch Cancer Society Fellowship (BUIT-2013-5847) to SJES, a Wellcome Trust PhD studentship to I.K and Core grant funding from the Wellcome Trust Core (092096) and CRUK (C6946/A14492).