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Induction and Analysis of Epithelial to Mesenchymal Transition
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ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through

Sarah Theresa Boyle1, Valentina Poltavets1, Jasreen Kular1

  • 1Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.

Nature Cell Biology
|May 27, 2020
PubMed

Insights

Breast cancer growth is fueled by a pathway involving Rho-associated kinase (ROCK) and protein-kinase-R-like endoplasmic reticulum kinase (PERK). This axis educates cancer-associated fibroblasts (CAFs), promoting tumor progression and offering new therapeutic targets.

Area of Science:

  • Oncology
  • Cell Biology
  • Cancer Microenvironment Research

Background:

  • Cancers extensively utilize their microenvironment to facilitate tumor growth.
  • The precise molecular mechanisms governing cancer-microenvironment interactions remain incompletely understood.
  • Identifying these mechanisms is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which mammary tumor epithelium interacts with and educates cancer-associated fibroblasts (CAFs).
  • To identify key signaling pathways and factors involved in cancer-microenvironment crosstalk.
  • To explore the therapeutic potential of targeting identified pathways in breast cancer.

Main Methods:

  • Investigated the role of Rho-associated kinase (ROCK) in mammary tumor cells.
  • Analyzed the activation of protein-kinase-R-like endoplasmic reticulum kinase (PERK) downstream of ROCK.
  • Identified cysteine-rich with EGF-like domains 2 (CRELD2) as a key paracrine factor using patient and mouse tumor samples.
  • Examined the regulation of CRELD2 by ATF4 and the impact of CRELD2 depletion on tumor progression.

Main Results:

  • ROCK in the mammary tumor epithelium activates PERK.
  • Activated PERK leads to the recruitment and education of tumor-promoting CAFs.
  • CRELD2 is identified as the paracrine mediator of PERK-driven CAF education.
  • The ROCK-PERK-ATF4-CRELD2 signaling axis was found to drive breast cancer progression.

Conclusions:

  • The paracrine axis involving ROCK, PERK, ATF4, and CRELD2 plays a significant role in promoting breast cancer progression.
  • Targeting this axis could represent a novel therapeutic strategy for breast cancer.
  • Understanding these molecular interactions is vital for advancing cancer treatment.

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