Mechanical cell competition kills cells via induction of lethal p53 levels.
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 (scrib(KD)) are hypersensitive to compaction, that interaction with wild-type cells causes their compaction and that crowding is sufficient for scrib(KD) 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.
The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Laura
L
Wagstaff
The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Maja
M
Goschorska
The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Kasia
K
Kozyrska
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, 75005 Paris, France.
Guillaume
G
Duclos
The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Iwo
I
Kucinski
Pharmacology Department, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
Anatole
0000-0002-1326-6305
A
Chessel
The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Lea
L
Hampton-O'Neil
The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Charles R
0000-0002-3528-458X
CR
Bradshaw
The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
George E
GE
Allen
The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Emma L
EL
Rawlins
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, 75005 Paris, France.
Pascal
0000-0002-8554-882X
P
Silberzan
Pharmacology Department, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
Rafael E
RE
Carazo Salas
The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Eugenia
E
Piddini
D000818:Animals; D017209:Apoptosis; D001696:Biomechanical Phenomena; D002450:Cell Communication; D004285:Dogs; D004330:Drosophila / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells / Q000737:chemistry* / Q000166:cytology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
D029721:Drosophila Proteins; D008565:Membrane Proteins; C404683:Scrib protein, Drosophila; D016159:Tumor Suppressor Protein p53; D054460:rho-Associated Kinases