ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism
Menée à partir de l'analyse de tissus mammaires cancéreux ou sains et menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel l'activation sélective (induite par la kinase ROCK) de la voie de signalisation de la kinase PERK favorise la modification des fibroblastes et la progression tumorale via un processus dépendant de la protéine CRELD2
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.