Apoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death

Florian J. Bock (), Egor Sedov, Elle Koren, Anna L. Koessinger, Catherine Cloix, Désirée Zerbst, Dimitris Athineos, Jayanthi Anand, Kirsteen J. Campbell, Karen Blyth, Yaron Fuchs and Stephen W. G. Tait ()
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Florian J. Bock: Cancer Research UK Beatson Institute
Egor Sedov: Technion Israel Institute of Technology
Elle Koren: Technion Israel Institute of Technology
Anna L. Koessinger: Cancer Research UK Beatson Institute
Catherine Cloix: Cancer Research UK Beatson Institute
Désirée Zerbst: Cancer Research UK Beatson Institute
Dimitris Athineos: Cancer Research UK Beatson Institute
Jayanthi Anand: Cancer Research UK Beatson Institute
Kirsteen J. Campbell: Cancer Research UK Beatson Institute
Karen Blyth: Cancer Research UK Beatson Institute
Yaron Fuchs: Technion Israel Institute of Technology
Stephen W. G. Tait: Cancer Research UK Beatson Institute

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Damaged or superfluous cells are typically eliminated by apoptosis. Although apoptosis is a cell-autonomous process, apoptotic cells communicate with their environment in different ways. Here we describe a mechanism whereby cells under apoptotic stress can promote survival of neighbouring cells. We find that upon apoptotic stress, cells release the growth factor FGF2, leading to MEK-ERK-dependent transcriptional upregulation of pro-survival BCL-2 proteins in a non-cell autonomous manner. This transient upregulation of pro-survival BCL-2 proteins protects neighbouring cells from apoptosis. Accordingly, we find in certain cancer types a correlation between FGF-signalling, BCL-2 expression and worse prognosis. In vivo, upregulation of MCL-1 occurs in an FGF-dependent manner during skin repair, which regulates healing dynamics. Importantly, either co-treatment with FGF-receptor inhibitors or removal of apoptotic stress restores apoptotic sensitivity to cytotoxic therapy and delays wound healing. These data reveal a pathway by which cells under apoptotic stress can increase resistance to cell death in surrounding cells. Beyond mediating cytotoxic drug resistance, this process also provides a potential link between tissue damage and repair.

Date: 2021
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DOI: 10.1038/s41467-021-26613-0

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