Cell Competition Drives the Growth of Intestinal Adenomas in Drosophila.

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.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).This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.cub.2015.12.04

Cell Competition Modifies Adult Stem Cell and Tissue Population Dynamics in a JAK-STAT-Dependent Manner.

Throughout their lifetime, cells may suffer insults that reduce their fitness and disrupt their function, and it is unclear how these potentially harmful cells are managed in adult tissues. We address this question using the adult Drosophila posterior midgut as a model of homeostatic tissue and ribosomal Minute mutations to reduce fitness in groups of cells. We take a quantitative approach combining lineage tracing and biophysical modeling and address how cell competition affects stem cell and tissue population dynamics. We show that healthy cells induce clonal extinction in weak tissues, targeting both stem and differentiated cells for elimination. We also find that competition induces stem cell proliferation and self-renewal in healthy tissue, promoting selective advantage and tissue colonization. Finally, we show that winner cell proliferation is fueled by the JAK-STAT ligand Unpaired-3, produced by Minute(-/+) cells in response to chronic JNK stress signaling.This work was supported by a Cancer Research UK Programme Grant (E.P. and G.K. A12460), a Royal Society University Research fellowship to E.P. (UF090580), an EMBO Long-Term Fellowship (ALTF 1476-2012), NWO Rubicon grant (825.12.027) and a Dutch Cancer Society Fellowship (BUIT-2013-5847) to S.J.E.S, a Wellcome Trust PhD studentships to IK and Core grant funding from the Wellcome Trust Core (092096) and CRUK (C6946/A14492).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.devcel.2015.06.01