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

Shunsuke Kon, Kojiro Ishibashi, Hiroto Katoh, Sho Kitamoto, Takanobu Shirai, Shinya Tanaka, Mihoko Kajita, Susumu Ishikawa, Hajime Yamauchi, Yuta Yako, Tomoko Kamasaki, Tomohiro Matsumoto, Hirotaka Watanabe, Riku Egami, Ayana Sasaki, Atsuko Nishikawa, Ikumi Kameda, Takeshi Maruyama, Rika Narumi, Tomoko Morita & 19 others Yoshiteru Sasaki, Ryosuke Enoki, Sato Honma, Hiromi Imamura, Masanobu Oshima, Tomoyoshi Soga, Jun Ichi Miyazaki, Michael R. Duchen, Jin Min Nam, Yasuhito Onodera, Shingo Yoshioka, Junichi Kikuta, Masaru Ishii, Masamichi Imajo, Eisuke Nishida, Yoichiro Fujioka, Yusuke Ohba, Toshiro Sato, Yasuyuki Fujita

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)530-541
Number of pages12
JournalNature Cell Biology
Volume19
Issue number5
DOIs
Publication statusPublished - 2017 May 1

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Epithelial Cells
Filamins
Mitochondrial Membrane Potential
Intestinal Mucosa
Lactic Acid
Neoplasms
Carcinogenesis
Up-Regulation
Epithelium
Glucose

ASJC Scopus subject areas

  • Cell Biology

Cite this

Kon, S., Ishibashi, K., Katoh, H., Kitamoto, S., Shirai, T., Tanaka, S., ... Fujita, Y. (2017). Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes. Nature Cell Biology, 19(5), 530-541. https://doi.org/10.1038/ncb3509

Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes. / Kon, Shunsuke; Ishibashi, Kojiro; Katoh, Hiroto; Kitamoto, Sho; Shirai, Takanobu; Tanaka, Shinya; Kajita, Mihoko; Ishikawa, Susumu; Yamauchi, Hajime; Yako, Yuta; Kamasaki, Tomoko; Matsumoto, Tomohiro; Watanabe, Hirotaka; Egami, Riku; Sasaki, Ayana; Nishikawa, Atsuko; Kameda, Ikumi; Maruyama, Takeshi; Narumi, Rika; Morita, Tomoko; Sasaki, Yoshiteru; Enoki, Ryosuke; Honma, Sato; Imamura, Hiromi; Oshima, Masanobu; Soga, Tomoyoshi; Miyazaki, Jun Ichi; Duchen, Michael R.; Nam, Jin Min; Onodera, Yasuhito; Yoshioka, Shingo; Kikuta, Junichi; Ishii, Masaru; Imajo, Masamichi; Nishida, Eisuke; Fujioka, Yoichiro; Ohba, Yusuke; Sato, Toshiro; Fujita, Yasuyuki.

In: Nature Cell Biology, Vol. 19, No. 5, 01.05.2017, p. 530-541.

Research output: Contribution to journalArticle

Kon, S, Ishibashi, K, Katoh, H, Kitamoto, S, Shirai, T, Tanaka, S, Kajita, M, Ishikawa, S, Yamauchi, H, Yako, Y, Kamasaki, T, Matsumoto, T, Watanabe, H, Egami, R, Sasaki, A, Nishikawa, A, Kameda, I, Maruyama, T, Narumi, R, Morita, T, Sasaki, Y, Enoki, R, Honma, S, Imamura, H, Oshima, M, Soga, T, Miyazaki, JI, Duchen, MR, Nam, JM, Onodera, Y, Yoshioka, S, Kikuta, J, Ishii, M, Imajo, M, Nishida, E, Fujioka, Y, Ohba, Y, Sato, T & Fujita, Y 2017, 'Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes', Nature Cell Biology, vol. 19, no. 5, pp. 530-541. https://doi.org/10.1038/ncb3509
Kon, Shunsuke ; Ishibashi, Kojiro ; Katoh, Hiroto ; Kitamoto, Sho ; Shirai, Takanobu ; Tanaka, Shinya ; Kajita, Mihoko ; Ishikawa, Susumu ; Yamauchi, Hajime ; Yako, Yuta ; Kamasaki, Tomoko ; Matsumoto, Tomohiro ; Watanabe, Hirotaka ; Egami, Riku ; Sasaki, Ayana ; Nishikawa, Atsuko ; Kameda, Ikumi ; Maruyama, Takeshi ; Narumi, Rika ; Morita, Tomoko ; Sasaki, Yoshiteru ; Enoki, Ryosuke ; Honma, Sato ; Imamura, Hiromi ; Oshima, Masanobu ; Soga, Tomoyoshi ; Miyazaki, Jun Ichi ; Duchen, Michael R. ; Nam, Jin Min ; Onodera, Yasuhito ; Yoshioka, Shingo ; Kikuta, Junichi ; Ishii, Masaru ; Imajo, Masamichi ; Nishida, Eisuke ; Fujioka, Yoichiro ; Ohba, Yusuke ; Sato, Toshiro ; Fujita, Yasuyuki. / Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes. In: Nature Cell Biology. 2017 ; Vol. 19, No. 5. pp. 530-541.
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AU - Tanaka, Shinya

AU - Kajita, Mihoko

AU - Ishikawa, Susumu

AU - Yamauchi, Hajime

AU - Yako, Yuta

AU - Kamasaki, Tomoko

AU - Matsumoto, Tomohiro

AU - Watanabe, Hirotaka

AU - Egami, Riku

AU - Sasaki, Ayana

AU - Nishikawa, Atsuko

AU - Kameda, Ikumi

AU - Maruyama, Takeshi

AU - Narumi, Rika

AU - Morita, Tomoko

AU - Sasaki, Yoshiteru

AU - Enoki, Ryosuke

AU - Honma, Sato

AU - Imamura, Hiromi

AU - Oshima, Masanobu

AU - Soga, Tomoyoshi

AU - Miyazaki, Jun Ichi

AU - Duchen, Michael R.

AU - Nam, Jin Min

AU - Onodera, Yasuhito

AU - Yoshioka, Shingo

AU - Kikuta, Junichi

AU - Ishii, Masaru

AU - Imajo, Masamichi

AU - Nishida, Eisuke

AU - Fujioka, Yoichiro

AU - Ohba, Yusuke

AU - Sato, Toshiro

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