ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism
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
Nature Cell Biology | NATURE PUBLISHING GROUP | Published : 2020
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..View full abstract
We thank J. Visvader for mouse mammary cancer tissue; P. Thomas for providing CRISPR vector pDG461; and M. White for assistance in designing CRISPR guides. The PyMT mammary cancer cell line was provided by K. Blyth through SEARCHBreast (https://searchbreast.org/).This research was supported by the NHMRC (to M.S.S., P.T., S.M.P., A.F.L. and M.K.), ARC (to M.S.S. and P.T.), the Cancer Councils of South Australia (M.S.S.) and New South Wales (P.T.), the RAH Research Fund (M.S.S.) and the Fay Fuller Foundation (S.M.P). S.T.B. was supported by a RAH Research Committee Early Career Fellowship. We thank donors to the Health Services Charitable Gifts Board of SA and the Australian Cancer Research Foundation (Cancer Discovery Accelerator) for funding the imaging equipment used.