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.

人们普遍认为，癌症会利用微环境来促进它们的生长。然而，癌症-微环境相互作用的分子机制仍然不清楚。在这里，我们显示乳腺肿瘤上皮中的 Rho 相关激酶 (ROCK) 选择性地激活蛋白激酶-R 样内质网激酶 (PERK)，导致促肿瘤癌相关成纤维细胞 (CAF) 的募集和持续培养，它们是癌症微环境的一部分。对患者和小鼠肿瘤的分析表明，富含半胱氨酸和 EGF 样结构域 2 (CRELD2) 是 ROCK 下游 PERK 介导的 CAF 教育的旁分泌因子。我们发现CRELD2受 PERK 调节的 ATF4 调节，消耗 CRELD2 抑制肿瘤进展，表明旁分泌 ROCK-PERK-ATF4-CRELD2 轴促进乳腺癌的进展，对癌症治疗有影响。