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

Bock, F. J. et al. (2021) Apoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death. Nature Communications, 12, 6572. (doi: 10.1038/s41467-021-26613-0) (PMID:34772930) (PMCID:PMC8590049)

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.

• Item Type: Articles
• Additional Information: This work was supported by Cancer Research UK grant C40872/A2014 (S.W.G.T), CRUK core funding A29799 to K.B. and a Tenovus small pilot grant (F.J.B). The authors would like to thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17196), with particular thanks to the Beatson Advanced Imaging Resource, Biological Services Unit, Histology and Molecular Technologies.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bock, Dr Florian and Blyth, Professor Karen and Koessinger, Dr Anna and Campbell, Dr Kirsteen and Zerbst, Désirée and Athineos, Mr Dimitris and Tait, Professor Stephen and Cloix, Dr Catherine
• Authors: Bock, F. J., Sedov, E., Koren, E., Koessinger, A. L., Cloix, C., Zerbst, D., Athineos, D., Anand, J., Campbell, K. J., Blyth, K., Fuchs, Y., and Tait, S. W.G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Communications 12: 6572
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
172007		Apoptosis as an oncogenic process: understanding and exploiting its dark-side	Stephen Tait	Cancer Research UK (CRUK)	C40872/A20145	Institute of Cancer Sciences