Hic-5 regulates fibrillar adhesion formation to control tumor extracellular matrix remodeling through interaction with tensin1

Abstract

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.

Identifying the key genes and microRNAs in prostate cancer bone metastasis by bioinformatics analysis

“…TNS1 was a focal adhesion molecule. Hic‐5 (TGFβ1i1) could control tumor extracellular matrix remodeling through interaction with TNS1 [50]. Most studies suggested that STAB1 was an oncogene and up‐regulated in many cancers [51].…”

Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer

“…Furthermore, we identified Hic-5 to be associated with the phenotypical and functional changes of both CD8 + T cells and F4/80 macrophages. Hic-5 has been recently identified as a crucial sensor of ECM remodelling by promoting fibrillar adhesion formation 44…”

Integrin trafficking in cells and tissues

“…In contrast, nutrient depletion induces α5β1-integrin translocation to tensin-dependent fibrillar adhesions, from which ligand- and tensin-bound integrins and ECM components are endocytosed to lysosomes to provide cell nutrients 90 . In cancer-associated fibroblasts (CAFs), interactions between Src-phosphorylated Hic-5 (also known as TGB1I1), β1-integrin and tensin1 stabilise β1-integrin on the cell surface, preventing receptor internalisation to lysosomes 91 . In starved human mammary epithelial cells, enhanced β4-integrin expression and endocytosis expedite laminin uptake and degradation in LAMP1-positive vesicles to generate the nutrients required for mammalian target of rapamycin complex 1 (mTORC1) activation and cell survival 92 .…”