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
  • 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. [email protected].
  • 10. Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia. [email protected].
  • 11. Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia. [email protected].
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.

Products