Inhibition of collagen receptor Discoidin Domain Receptor-1 (DDR1) Reduces Cell Survival, Homing and Colonization in Lung Cancer Bone Metastasis
Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur 83 patients atteints d'un cancer du poumon, cette étude met en évidence le rôle joué par le récepteur DDR1 de liaison au collagène dans le développement de métastases osseuses
Purpose: We investigated the role of the collagen binding receptor, discoidin domain receptor-1 (DDR1), in the initiation and development of bone metastasis. Experimental Design:We performed westernblot analysis and phosphorylation status in a panel of human lung cancer cell lines and immunohistochemical analysis in a cohort of 83 lung cancer specimens. Adhesion, chemotaxis, invasiveness, metalloproteolytic, osteoclastogenic and apoptotic assays were performed in DDR1 silenced cells. In vivo, metastatic osseous homing and colonization was assessed in a murine model of metastasis. Results:DDR1 was expressed in a panel of human lung cancer cell lines and high DDR1 levels in human lung tumors were associated with poor survival. Knock-down (shDDR1) cells displayed unaltered growth kinetics in vitro and in vivo. In contrast, shDDR1 cells showed reduced invasiveness in collagen matrices and increased basal and induced apoptosis in vitro. More importantly, conditioned media of DDR1 knock down cells decreased osteoclastogenic activity in vitro. Consequently, in a model of tumor metastasis to bone, lack of DDR1 showed decreased metastatic activity associated with reduced tumor burden and osteolytic lesions. These effects were consistent with a substantial reduction in the number of cells reaching the bone compartment. Moreover, intratibial injection of shDDR1 cells significantly decreased bone tumor burden, suggesting impaired colonization ability that was highly dependent on the bone microenvironment. Conclusions: Disruption of DDR1 hampers tumor cell survival, leading to impaired early tumor-bone engagement during skeletal homing. Furthermore, inhibition of DDR1 crucially alters bone colonization. We suggest that DDR1 represents a novel therapeutic target involved in bone metastasis.