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Nat Cell Biol. 2017 May;19(5):530-541. doi: 10.1038/ncb3509. Epub 2017 Apr 17.

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

Author information

1
Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Sapporo 060-0815, Japan.
2
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
3
Photonic Bioimaging Section, Research Center for Cooperative Projects, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
4
Department of Chronomedicine, Hokkaido University Graduate School of Medicine, Sapporo 060-0810, Japan.
5
Precursory Research for Embryonic Science and Technology (PRESTO), Japan, Science and Technology Agency (JST), Saitama 332-0012, Japan.
6
Laboratory of Functional Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
7
Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
8
Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan.
9
Department of Nutrition and Physiological Chemistry, Osaka University Medical School, Osaka 565-0871, Japan.
10
Research Department of Cell &Developmental Biology, University College London, London WC1E 6BT, UK.
11
Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 060-8648, Japan.
12
Department of Molecular Biology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
13
Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
14
Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Kyoto 606-8315, Japan.
15
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
16
Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
17
Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-0016, Japan.

Abstract

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.

PMID:
28414314
DOI:
10.1038/ncb3509
[Indexed for MEDLINE]

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