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ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism


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.

Type Journal
ISBN 1476-4679 (Electronic) 1465-7392 (Linking)
Authors Boyle, S. T.; Poltavets, V.; Kular, J.; Pyne, N. T.; Sandow, J. J.; Lewis, A. C.; Murphy, K. J.; Kolesnikoff, N.; Moretti, P. A. B.; Tea, M. N.; Tergaonkar, V.; Timpson, P.; Pitson, S. M.; Webb, A. I.; Whitfield, R. J.; Lopez, A. F.; Kochetkova, M.; Samuel, M. S.
Responsible Garvan Author Prof Paul Timpson
Published Date 2020-07-31
Published Volume 22
Published Issue 7
Published Pages 882-895
Status Published in-print
DOI 10.1038/s41556-020-0539-3
URL link to publisher's version