ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism
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
WEHI Research Division(s)
Advanced Technology And Biology
PubMed ID
32451439
NHMRC Grants
NHMRC/GNT1103712 NHMRC/GNT1145319
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
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