2. Academic Validation
  3. ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism

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

  • Nat Cell Biol. 2020 Jul;22(7):882-895. doi: 10.1038/s41556-020-0523-y.
Sarah Theresa Boyle 1,  Valentina Poltavets 1,  Jasreen Kular 1,  Natasha Theresa Pyne 1,  Jarrod John Sandow 2 3,  Alexander Charles Lewis 1 4,  Kendelle Joan Murphy 5,  Natasha Kolesnikoff 1,  Paul Andre Bartholomew Moretti 1,  Melinda Nay Tea 1,  Vinay Tergaonkar 1 6,  Paul Timpson 5,  Stuart Maxwell Pitson 1 7,  Andrew Ian Webb 2 3,  Robert John Whitfield 8,  Angel Francisco Lopez 1 7,  Marina Kochetkova 9,  Michael Susithiran Samuel 10 11
Affiliations

Affiliations

  • 1 Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.
  • 2 Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • 3 Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • 4 Translational Haematology Program, Peter McCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 5 The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, St Vincent's Clinical School, University of NSW, Sydney, New South Wales, Australia.
  • 6 Institute of Molecular and Cell Biology, A*STAR and Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 7 Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.
  • 8 Breast, Endocrine and Surgical Oncology Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
  • 9 Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia. Marina.Kochetkova@unisa.edu.au.
  • 10 Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia. Michael.Samuel@unisa.edu.au.
  • 11 Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia. Michael.Samuel@unisa.edu.au.
PMID: 32451439 DOI: 10.1038/s41556-020-0523-y
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.

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