ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism
- Author(s)
- Boyle, ST; Poltavets, V; Kular, J; Pyne, NT; Sandow, JJ; Lewis, AC; Murphy, KJ; Kolesnikoff, N; Moretti, PAB; Tea, MN; Tergaonkar, V; Timpson, P; Pitson, SM; Webb, AI; Whitfield, RJ; Lopez, AF; Kochetkova, M; Samuel, MS;
- Journal Title
- Nature Cell Biology
- Publication Type
- Journal epub ahead of print
- Abstract
- It is well accepted that cancers co-opt the microenvironment for their growth. However, the molecular mechanisms that underlie cancer-microenvironment interactions are still poorly defined. Here, we show that Rho-associated kinase (ROCK) in the mammary tumour epithelium selectively actuates protein-kinase-R-like endoplasmic reticulum kinase (PERK), causing the recruitment and persistent education of tumour-promoting cancer-associated fibroblasts (CAFs), which are part of the cancer microenvironment. An analysis of tumours from patients and mice reveals that cysteine-rich with EGF-like domains 2 (CRELD2) is the paracrine factor that underlies PERK-mediated CAF education downstream of ROCK. We find that CRELD2 is regulated by PERK-regulated ATF4, and depleting CRELD2 suppressed tumour progression, demonstrating that the paracrine ROCK-PERK-ATF4-CRELD2 axis promotes the progression of breast cancer, with implications for cancer therapy.
- Publisher
- NPG
- Research Division(s)
- Advanced Technology And Biology
- PubMed ID
- 32451439
- Publisher's Version
- https://doi.org/10.1038/s41556-020-0523-y
- NHMRC Grants
- NHMRC/GNT1103712, NHMRC/GNT1145319,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2020-06-03 09:37:45
Last Modified: 2020-06-03 09:45:02