ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism
- 25 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 22 (7), 882-895
- https://doi.org/10.1038/s41556-020-0523-y
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.Keywords
Funding Information
- Royal Adelaide Hospital Research Fund
- Australian Government Research Training Program
- Department of Health | National Health and Medical Research Council (GNT1145319, GNT1103712)
- Department of Education and Training | Australian Research Council (FT120100132)
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