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.
Keywords: Drosophila; Hippo signaling; JNK signaling; Yki/YAP/TAZ; adenomatous polyposis coli (APC); apoptosis; cancer; cell competition; cell death; intestinal adenomas; posterior midgut; tumor microenvironment.
Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.