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

F.J. Bock*, E. Sedov, E. Koren, A.L. Koessinger, C. Cloix, D. Zerbst, D. Athineos, J. Anand, K.J. Campbell, K. Blyth, Y. Fuchs, S.W.G. Tait*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.Apoptosis is a cellular process that eliminates damaged or superfluous cells. Here the authors show that cells undergoing apoptotic stresss secrete the growth factor FGF2, which upregulates pro-survival BCL-2 proteins in neighbouring cells, thereby promoting their survival.
Original languageEnglish
Article number6572
Number of pages14
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 12 Nov 2021

Keywords

  • FIBROBLAST-GROWTH-FACTOR
  • STEM-CELLS
  • MEMBRANE PERMEABILIZATION
  • ANTITUMOR-ACTIVITY
  • GENE-PRODUCT
  • KINASE
  • INHIBITOR
  • BCL-2
  • EXPRESSION
  • SURVIVAL

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