Mechanical cell competition kills cells via induction of lethal p53 levels

Laura Wagstaff, Maja Goschorska, Kasia Kozyrska, Guillaume Duclos, Iwo Kucinski, Anatole Chessel, Lea Hampton-O’Neil, Charles R. Bradshaw, George E. Allen, Emma L. Rawlins, Pascal Silberzan, Rafael E. Carazo Salas and Eugenia Piddini ()
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Laura Wagstaff: University of Cambridge
Maja Goschorska: University of Cambridge
Kasia Kozyrska: University of Cambridge
Guillaume Duclos: Laboratoire PhysicoChimie Curie, Institut Curie, Paris Sciences et Lettres Research University – Sorbonne Universités, Université Pierre et Marie Curie – Centre National de la recherche Scientifique – Equipe labellisée Ligue Contre le Cancer
Iwo Kucinski: University of Cambridge
Anatole Chessel: University of Cambridge
Lea Hampton-O’Neil: University of Cambridge
Charles R. Bradshaw: University of Cambridge
George E. Allen: University of Cambridge
Emma L. Rawlins: University of Cambridge
Pascal Silberzan: Laboratoire PhysicoChimie Curie, Institut Curie, Paris Sciences et Lettres Research University – Sorbonne Universités, Université Pierre et Marie Curie – Centre National de la recherche Scientifique – Equipe labellisée Ligue Contre le Cancer
Rafael E. Carazo Salas: University of Cambridge
Eugenia Piddini: University of Cambridge

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Cell competition is a quality control mechanism that eliminates unfit cells. How cells compete is poorly understood, but it is generally accepted that molecular exchange between cells signals elimination of unfit cells. Here we report an orthogonal mechanism of cell competition, whereby cells compete through mechanical insults. We show that MDCK cells silenced for the polarity gene scribble (scribKD) are hypersensitive to compaction, that interaction with wild-type cells causes their compaction and that crowding is sufficient for scribKD cell elimination. Importantly, we show that elevation of the tumour suppressor p53 is necessary and sufficient for crowding hypersensitivity. Compaction, via activation of Rho-associated kinase (ROCK) and the stress kinase p38, leads to further p53 elevation, causing cell death. Thus, in addition to molecules, cells use mechanical means to compete. Given the involvement of p53, compaction hypersensitivity may be widespread among damaged cells and offers an additional route to eliminate unfit cells.

Date: 2016
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DOI: 10.1038/ncomms11373

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