CAFs衍生的YAP1骨膜炎轴形成纤维化肿瘤微环境，促进转移性肺肿瘤生长
The CAFs-derived YAP1-periostin axis forms a fibrotic tumor microenvironment to promote metastatic lung tumor growth.
摘要(中文译文)
非小细胞肺癌（NSCLC）患者预后不良的主要原因是转移；然而，肿瘤微环境（TME）中癌症相关成纤维细胞（CAFs）介导的潜在机制尚知之甚少。我们开展了全面的分子和细胞分析，包括RNA测序、免疫组织化学、共培养实验和基因小鼠模型，以研究CD248-骨膜蛋白-整合素β1（ITGB1）轴在NSCLC转移中的作用。我们证明CD248阳性CAFs是NSCLC转移的关键调控因子。RNA测序和临床样本分析显示，CAFs中CD248的表达与骨膜蛋白（由POSTN编码）分泌增加呈正相关。在CAFs中，骨膜蛋白表达升高与NSCLC患者的淋巴结转移（p = 0.002）、晚期肿瘤分期（p = 0.0039）和较差的总生存期（p < 0.05）密切相关。在机制上，CD248通过促进YAP1的核转位并调控POSTN启动子活性以增加骨膜蛋白表达，从而导致CAFs中YAP1激活。功能实验表明，CAFs分泌的骨膜蛋白与NSCLC细胞中的ITGB1结合，触发FAK/Src信号通路，引起上皮-间质转化（EMT）样表型改变，并促进NSCLC细胞侵袭和迁移。此外，骨膜蛋白促进I型胶原沉积并增加细胞外基质（ECM）硬度，进一步放大CD248阳性CAFs中YAP1驱动的骨膜蛋白分泌，形成促转移的正反馈环路。成纤维细胞特异性CD248缺失或POSTN敲除小鼠在体内表现出NSCLC转移性肿瘤生长显著减少。这伴随TME中ECM硬度降低、EMT样表型改变减少以及I型胶原沉积减少。我们的结果共同提示，CD248-YAP1-骨膜蛋白-ITGB1轴促成了NSCLC中的促转移反馈环路，表明靶向该轴可能是预防NSCLC转移的可行治疗策略。
Abstract
The primary cause of poor prognosis in non-small cell lung cancer (NSCLC) patients is metastasis; however, little is known about the underlying mechanisms mediated by cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME). We conducted comprehensive molecular and cellular analyses, including RNA sequencing, immunohistochemistry, coculture experiments, and genetic mouse models, to investigate the role of the CD248-periostin-integrin β1 (ITGB1) axis in NSCLC metastasis. We demonstrated that CD248 CAFs are key regulators of NSCLC metastasis. RNA sequencing and clinical sample analysis revealed that CD248 expression in CAFs was positively correlated with increased secretion of periostin (encoded by POSTN). In CAFs, elevated periostin expression is strongly linked to lymph node metastasis (p = 0.002), advanced tumor stage (p = 0.0039), and poor overall survival (p < 0.05) in patients with NSCLC. By promoting the nuclear translocation of YAP1 and regulating POSTN promoter activity to increase periostin expression, CD248 mechanistically causes YAP1 activation in CAFs. According to functional tests, CAFs secreted periostin binds to ITGB1 in NSCLC cells, triggering the FAK/Src signaling pathway to cause epithelial-mesenchymal transition (EMT)-like phenotypic changes and promote NSCLC cell invasion and migration. Additionally, periostin promotes collagen I deposition and increases extracellular matrix (ECM) stiffness, which further amplifies YAP1-driven periostin secretion from CD248 CAFs, resulting in the formation of a prometastatic positive feedback loop. Fibroblast-specific CD248 deletion or POSTN knockout mice exhibit dramatically reduced metastatic tumor growth in NSCLC in vivo. This is accompanied by decreased ECM stiffness in the TME, decreased EMT-like phenotypic changes, and decreased collagen I deposition. Our results collectively suggested a CD248-YAP1-Periostin-ITGB1 axis that contributes to a prometastatic feedback loop in NSCLC, indicating that focusing on this axis may be a viable therapeutic approach to prevent NSCLC metastasis.
如何引用
AMA
Jieheng Wu, Xuanyin Wang, Zeyang Yang, Ying Zhang, Maoqin Lu, Lu Wang, et al. The CAFs-derived YAP1-periostin axis forms a fibrotic tumor microenvironment to promote metastatic lung tumor growth.. Journal of translational medicine. 2026; doi:10.1186/s12967-026-08664-3.
APA
Jieheng Wu, Xuanyin Wang, Zeyang Yang, Ying Zhang, Maoqin Lu, Lu Wang, et al (2026). The CAFs-derived YAP1-periostin axis forms a fibrotic tumor microenvironment to promote metastatic lung tumor growth.. Journal of translational medicine. https://doi.org/10.1186/s12967-026-08664-3
GB/T 7714
Jieheng Wu, Xuanyin Wang, Zeyang Yang, Ying Zhang, Maoqin Lu, Lu Wang, et al. The CAFs-derived YAP1-periostin axis forms a fibrotic tumor microenvironment to promote metastatic lung tumor growth.[J]. Journal of translational medicine, 2026 doi:10.1186/s12967-026-08664-3.
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