Tumor DDR1 deficiency reduces liver metastasis by colon carcinoma and impairs stromal reaction.

Abstract

Colorectal cancer (CRC) colonization of the liver and its further metastatic growth are the result of complex interaction between the tumor cell, the collagenous extracellular matrix (ECM) and the hepatic sinusoidal cells (SCs). Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor activated by collagen and a bad prognosis factor in cancer. DDR1 signaling regulates key cell functions for tumor development, such as proliferation, migration, invasion and metalloproteinases (MMPs) secretion. However, the mechanisms underlying the implication of DDR1 in the conformation of the metastatic niche in the liver remain poorly known. In this study, we used an experimental model of liver metastasis from CRC to investigate the role of DDR1 in the context of the pro-metastatic crosstalk between tumor cells and the hepatic stroma. Bioinformatics and immunohistochemical analysis revealed that DDR1 was highly expressed in tumor tissues from patients with primary CRC and hepatic CRC metastasis. Besides, DDR1 overexpression was associated with poor outcome. In vitro, SCs-derived soluble factors promoted DDR1 phosphorylation and MMP2 production by CRC cells. In vivo, tumor DDR1 participated in hepatic ECM remodeling by modulating the expression of collagen and MMP2, and stimulated the recruitment of stromal cells into the tumor microenvironment. In addition, tumor DDR1 favored SCs ability to modify the ECM organization by controlling the expression of collagen and MMPs. Altogether, our results show that tumor DDR1 plays an important role in the desmoplastic response of hepatic tumor microenvironment during CRC invasion and growth.