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Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes.

Shunsuke KonKojiro IshibashiHiroto KatohSho KitamotoTakanobu ShiraiShinya TanakaMihoko KajitaSusumu IshikawaHajime YamauchiYuta YakoTomoko KamasakiTomohiro MatsumotoHirotaka WatanabeRiku EgamiAyana SasakiAtsuko NishikawaIkumi KamedaTakeshi MaruyamaRika NarumiTomoko MoritaYoshiteru SasakiRyosuke EnokiSato HonmaHiromi ImamuraMasanobu OshimaTomoyoshi SogaJun-Ichi MiyazakiMichael R DuchenJin-Min NamYasuhito OnoderaShingo YoshiokaJunichi KikutaMasaru IshiiMasamichi ImajoEisuke NishidaYoichiro FujiokaYusuke OhbaToshiro SatoYasuyuki Fujita
Published in: Nature cell biology (2017)
Recent studies have revealed that newly emerging transformed cells are often apically extruded from epithelial tissues. During this process, normal epithelial cells can recognize and actively eliminate transformed cells, a process called epithelial defence against cancer (EDAC). Here, we show that mitochondrial membrane potential is diminished in RasV12-transformed cells when they are surrounded by normal cells. In addition, glucose uptake is elevated, leading to higher lactate production. The mitochondrial dysfunction is driven by upregulation of pyruvate dehydrogenase kinase 4 (PDK4), which positively regulates elimination of RasV12-transformed cells. Furthermore, EDAC from the surrounding normal cells, involving filamin, drives the Warburg-effect-like metabolic alteration. Moreover, using a cell-competition mouse model, we demonstrate that PDK-mediated metabolic changes promote the elimination of RasV12-transformed cells from intestinal epithelia. These data indicate that non-cell-autonomous metabolic modulation is a crucial regulator for cell competition, shedding light on the unexplored events at the initial stage of carcinogenesis.
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