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

Kon, S; Ishibashi, K; Katoh, H; Kitamoto, S; Shirai, T; Tanaka, S; Kajita, M; ... Fujita, Y; + view all (2017) Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes. Nature Cell Biology , 19 (5) pp. 530-541. 10.1038/ncb3509. Green open access

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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.

Type: Article
Title: Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/ncb3509
Publisher version: http://dx.doi.org/10.1038/ncb3509
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: https://discovery.ucl.ac.uk/id/eprint/1552720
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