Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) reduces cell survival, homing, and colonization in lung cancer bone metastasis.
OBJECTIVE
We investigated the role of the collagen-binding receptor discoidin domain receptor-1 (DDR1) in the initiation and development of bone metastasis.


METHODS
We conducted immunohistochemical analyses in a cohort of 83 lung cancer specimens and examined phosphorylation status in a panel of human lung cancer cell lines. Adhesion, chemotaxis, invasiveness, metalloproteolytic, osteoclastogenic, and apoptotic assays were conducted in DDR1-silenced cells. In vivo, metastatic osseous homing and colonization were 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. Knockdown (shDDR1) cells displayed unaltered growth kinetics in vitro and in vivo. In contrast, shDDR1 cells showed reduced invasiveness in collagen matrices and increased apoptosis in basal conditions and induced apoptosis in vitro. More importantly, conditioned media of DDR1-knockdown 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.
Adhesion and Metastasis Laboratory, Biomarkers Laboratory, Division of Oncology, Center for Applied Biomedical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.
Karmele
K
Valencia
Cristina
C
Ormazábal
Carolina
C
Zandueta
Diego
D
Luis-Ravelo
Iker
I
Antón
María J
MJ
Pajares
Jackeline
J
Agorreta
Luis M
LM
Montuenga
Susana
S
Martínez-Canarias
Birgit
B
Leitinger
Fernando
F
Lecanda
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001859:Bone Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary*; D001862:Bone Resorption / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival; D000070819:Discoidin Domain Receptor 1; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D010010:Osteoclasts / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases