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
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DOI：
10.1038/s41556-020-0523-y
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发表时间：
2020-05-25
影响因子：
21.3
通讯作者：
Samuel, Michael Susithiran
中科院分区：
文献类型：
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作者：
Boyle, Sarah Theresa;Poltavets, Valentina;Samuel, Michael Susithiran
波义耳等人表明，ROCK上调乳腺癌上皮细胞中的PERK信号传导，从而通过CRELD 2增强癌症相关成纤维细胞的募集和功能，以促进肿瘤发生。然而，癌症与微环境相互作用的分子机制仍然不清楚。在这里，我们表明，Rho相关激酶（ROCK）在乳腺肿瘤上皮细胞选择性激活蛋白激酶R样内质网激酶（PERK），导致招聘和持续教育的肿瘤促进癌症相关成纤维细胞（CAF），这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EGF样结构域2（CRELD 2）的半胱氨酸是ROCK下游PERK介导的CAF教育的基础的旁分泌因子。我们发现CRELD 2受PERK调节的ATF 4调节，并且耗尽CRELD 2抑制肿瘤进展，表明旁分泌ROCK-PERK-ATF 4-CRELD 2轴促进乳腺癌的进展，这对癌症治疗具有意义。
Boyle et al. show that ROCK upregulates PERK signalling in epithelia of breast cancer, thereby enhancing recruitment and function of cancer-associated fibroblasts through CRELD2 to promote tumourigenesis.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.