Mechanical cell competition kills cells via induction of lethal p53 levels

Area of Science:

• Cell biology
• Mechanobiology
• Cancer research

Background:

• Cell competition is a crucial quality control process for eliminating unfit cells.
• Existing understanding suggests molecular exchange mediates cell elimination during competition.
• The precise mechanisms driving cell competition remain incompletely understood.

Purpose of the Study:

• To investigate alternative mechanisms of cell competition beyond molecular signaling.
• To explore the role of mechanical forces in cell elimination.
• To elucidate the signaling pathways involved in mechanical cell competition.

Main Methods:

• Utilized MDCK cells with silenced polarity gene scribble (scrib(KD)).
• Investigated cell responses to compaction and crowding.
• Analyzed the role of tumor suppressor p53, Rho-associated kinase (ROCK), and stress kinase p38 in cell elimination.
• Examined molecular exchange versus mechanical insults in cell competition.

Main Results:

• Silenced scribble (scrib(KD)) cells exhibit hypersensitivity to mechanical compaction.
• Interaction with wild-type cells induces compaction in scrib(KD) cells.
• Cell crowding is sufficient to trigger elimination of scrib(KD) cells.
• Elevated tumor suppressor p53 is essential and sufficient for this crowding hypersensitivity.
• Compaction activates ROCK and p38, further increasing p53 levels and causing cell death.

Conclusions:

• A novel, orthogonal mechanism of cell competition mediated by mechanical insults has been identified.
• Mechanical forces, specifically compaction and crowding, can directly trigger cell elimination.
• Tumor suppressor p53 plays a critical role in mediating hypersensitivity to mechanical stress.
• This mechanical cell competition pathway, involving p53, may be a widespread mechanism for eliminating damaged cells.