The linearization of the stromal extracellular matrix (ECM) by cancer-associated fibroblasts (CAFs) facilitates tumor cell growth and metastasis. However, the mechanism by which the ECM is remodeled is not fully understood. Hic-5 (TGFβ1i1), a focal adhesion scaffold protein, has previously been reported to be crucial for stromal ECM deposition and remodeling in vivo. Herein we show that CAFs lacking Hic-5 exhibit a significant reduction in the ability to form fibrillar adhesions, a specialized form of focal adhesion that promote fibronectin fibrillogenesis. Hic-5 was found to promote fibrillar adhesion formation through a newly characterized interaction with tensin1. Furthermore, Src-dependent phosphorylation of Hic-5 facilitated the interaction with tensin1 to prevent β1 integrin internalization and trafficking to the lysosome. The interaction between Hic-5 and tensin1 was mechanosensitive, promoting fibrillar adhesion formation and fibronectin fibrillogenesis in a rigidity-dependent fashion. Importantly, this Src-dependent mechanism was conserved in three-dimensional (3D) ECM environments. Immunohistochemistry of tensin1 showed enrichment in CAFs in vivo, which was abrogated upon deletion of Hic-5. Interestingly, elevated Hic-5 expression correlates with reduced distant metastasis-free survival in patients with basal-like, HER2+ and grade 3 tumors. Thus, we have identified Hic-5 as a crucial regulator of ECM remodeling in CAFs by promoting fibrillar adhesion formation through a novel interaction with tensin1.

中文翻译：

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Hic-5通过与tensin1相互作用调节原纤维粘附形成，以控制肿瘤细胞外基质重塑。

癌相关成纤维细胞（CAF）对基质细胞外基质（ECM）的线性化促进了肿瘤细胞的生长和转移。但是，ECM重塑的机制尚未完全了解。以前已经报道了Hic-5（TGFβ11i1），一种粘着斑支架蛋白，对于基质ECM的体内沉积和体内重塑起着至关重要的作用。本文中，我们显示缺乏Hic-5的CAF在形成原纤维粘连的能力上显着降低，原纤维粘连是促进纤连蛋白原纤维形成的一种特殊形式。发现Hic-5通过与tensin1的新鉴定相互作用促进原纤维粘附的形成。此外，Hic-5的Src依赖性磷酸化促进了与tensin1的相互作用，从而阻止了β1整联蛋白的内在化和向溶酶体的运输。Hic-5和tensin1之间的相互作用是机械敏感性的，以依赖于刚性的方式促进纤维状粘连的形成和纤连蛋白的原纤维形成。重要的是，这种依赖于Src的机制在三维（3D）ECM环境中得以保留。tensin1的免疫组织化学显示体内CAF富集，在删除Hic-5后被废止。有趣的是，Hic-5表达升高与基底样，HER2 +和3级肿瘤患者的远处无转移生存率降低相关。因此，我们已经确定Hic-5是通过与tensin1的新相互作用促进原纤维粘附形成而成为CAF中ECM重塑的关键调节剂。这种依赖于Src的机制在三维（3D）ECM环境中得以保留。tensin1的免疫组织化学显示体内CAF富集，在删除Hic-5后被废止。有趣的是，Hic-5表达升高与基底样，HER2 +和3级肿瘤患者的远处无转移生存率降低相关。因此，我们已经确定Hic-5是通过与tensin1的新相互作用促进原纤维粘附形成而成为CAF中ECM重塑的关键调节剂。这种依赖于Src的机制在三维（3D）ECM环境中得以保留。tensin1的免疫组织化学显示体内CAF富集，在删除Hic-5后被废止。有趣的是，Hic-5表达升高与基底样，HER2 +和3级肿瘤患者的远处无转移生存率降低相关。因此，我们已经确定Hic-5是通过与tensin1的新相互作用促进原纤维粘附形成而成为CAF中ECM重塑的关键调节剂。HER2 +和3级肿瘤。因此，我们已经确定Hic-5是通过与tensin1的新相互作用促进原纤维粘附形成而成为CAF中ECM重塑的关键调节剂。HER2 +和3级肿瘤。因此，我们已经确定Hic-5是通过与tensin1的新相互作用促进原纤维粘附形成而成为CAF中ECM重塑的关键调节剂。