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https://hdl.handle.net/2440/126304
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Type: | Journal article |
Title: | ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism |
Author: | 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. |
Citation: | Nature Cell Biology, 2020; 22(7):882-895 |
Publisher: | Springer Nature |
Issue Date: | 2020 |
ISSN: | 1465-7392 1476-4679 |
Statement of Responsibility: | 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, and Michael Susithiran Samuel |
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: | Cells, Cultured Endoplasmic Reticulum Animals Humans Mice Breast Neoplasms Disease Models, Animal eIF-2 Kinase Cell Adhesion Molecules Extracellular Matrix Proteins Paracrine Communication Female Activating Transcription Factor 4 rho-Associated Kinases Cellular Reprogramming Cancer-Associated Fibroblasts |
Description: | Corrected by: Publisher Correction: ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism (Nature Cell Biology, (2020), 22, (908)). In the PDF version of this article originally published, a text label was omitted from Fig. 2g. The heading for the images in the right-hand column of Fig. 2g should be “R-PyMT + 4HT”. The error has been corrected in the PDF version of the paper. |
Rights: | Copyright © 2020, Springer Nature |
DOI: | 10.1038/s41556-020-0523-y |
Grant ID: | ARC NHMRC |
Published version: | http://dx.doi.org/10.1038/s41556-020-0523-y |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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