ROCK-mediated Selective Activation of PERK Signalling Causes Fibroblast Reprogramming and Tumour Progression Through a CRELD2-dependent Mechanism

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2020 May 27

PMID 32451439

Citations 35

Authors

Sarah Theresa Boyle

Valentina Poltavets

Jasreen Kular

Natasha Theresa Pyne

Jarrod John Sandow

Alexander Charles Lewis

Kendelle Joan Murphy

Natasha Kolesnikoff

Paul Andre Bartholomew Moretti

Melinda Nay Tea

Vinay Tergaonkar

Paul Timpson

Stuart Maxwell Pitson

Andrew Ian Webb

Robert John Whitfield

Angel Francisco Lopez

Marina Kochetkova

Michael Susithiran Samuel

Affiliations

Soon will be listed here.

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.

Citing Articles

CAF-Associated Genes in Breast Cancer for Novel Therapeutic Strategies.

Naito K, Sangai T, Yamashita K Biomedicines. 2024; 12(9).

PMID: 39335478 PMC: 11428270. DOI: 10.3390/biomedicines12091964.

Cysteine-rich with EGF-like domains 2 (CRELD2) is an endoplasmic reticulum stress-inducible angiogenic growth factor promoting ischemic heart repair.

Wu X, Zheng L, Reboll M, Hyde L, Mass E, Niessen H Nat Cardiovasc Res. 2024; 3(2):186-202.

PMID: 39196188 PMC: 11358006. DOI: 10.1038/s44161-023-00411-x.

Enhanced RHO-ROCK signaling is associated with CRELD2 production and fibroblast recruitment in cutaneous squamous cell carcinoma.

Pittar A, Buckley E, Boyle S, Ibbetson S, Samuel M Cytoskeleton (Hoboken). 2024; 81(12):864-871.

PMID: 38979935 PMC: 11615837. DOI: 10.1002/cm.21894.

MOTAI: A Novel Method for the Study of O-GalNAcylation and Complex O-Glycosylation in Cancer.

Yue S, Wang X, Wang L, Li J, Zhou Y, Chen Y Anal Chem. 2024; 96(28):11137-11145.

PMID: 38953491 PMC: 11257061. DOI: 10.1021/acs.analchem.3c05018.

Molecular characterization of the ER stress-inducible factor CRELD2.

Hinaga S, Kandeel M, Oh-Hashi K Cell Biochem Biophys. 2024; 82(2):1463-1475.

PMID: 38753249 DOI: 10.1007/s12013-024-01300-1.

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