Abstract 3964: Integrin α2-collagen I axis promotes proliferative and migratory phenotypes in intrahepatic cholangiocarcinoma

Abstract

Abstract Cholangiocarcinoma (CCA) is a deadly cancer of the bile duct and is considered an incurable disease with no efficacious treatment option. CCA arises as a consequence of chronic inflammation and tissue damage to the biliary epithelium. Thus, one of the crucial characteristics of CCA is its tumor microenvironment high in stromal extracellular matrices (ECMs), especially collagen I. Herein, the direct impact of collagen I on intrahepatic CCA (iCCA) cell lines were investigated. Our data demonstrate that iCCA cells mainly interact with collagen I, while cholangiocyte cells preferentially binds to fibronectin in cell adhesion assays. Correspondingly, iCCA cell lines exhibit over 20 fold-upregulation of ITGA2 gene, which encodes collagen-binding integrin α2, when compared with non-cancerous cholangiocyte cells. Furthermore, the result from the GEO dataset of 92 iCCA patients demonstrate that ITGA2 gene expression in iCCA tumors is 13 folds greater than their adjacent normal tissues and is positively correlated with expressions of two isoforms of collagen I gene, COL1A1 and COL1A2. Collagen I is also sufficient to drive proliferation of iCCA cells in a serum-restricted condition and this effect is mediated by integrin α2 as proven by ITGA2 silencing or α2β1-selective inhibitor treatment. In contrast to round-shaped, multicellular colonies of iCCA cells in clonogenic assays, iCCA colonies exhibit migratory phenotypes in the presence of collagen I. Likewise, this phenotype can be inhibited by α2β1-selective inhibitor treatment. Taken together, these data suggest that stromal collagen I could be one of the tumor microenvironmental factors directly facilitating iCCA progression. Thus, targeting the integrin α2-collagen I axis could be a promising therapeutic strategy for combating this cancer. Citation Format: Chotirat Rattanasinchai, Panida Navasumrit, Mathuros Ruchirawat. Integrin α2-collagen I axis promotes proliferative and migratory phenotypes in intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3964.