Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions

• Published in: Oncogene Vol. 40; no. 7; pp. 1284 - 1299
• Main Authors: Pantano, Francesco, Croset, Martine, Driouch, Keltouma, Bednarz-Knoll, Natalia, Iuliani, Michele, Ribelli, Giulia, Bonnelye, Edith, Wikman, Harriet, Geraci, Sandra, Bonin, Florian, Simonetti, Sonia, Vincenzi, Bruno, Hong, Saw See, Sousa, Sofia, Pantel, Klaus, Tonini, Giuseppe, Santini, Daniele, Clézardin, Philippe
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.02.2021; Nature Publishing Group; Nature Publishing Group [1987-....]
• Subjects: 13; 13/31; 13/51; 38; 38/109; 38/39; 38/77; 59; 59/5; 631/67/322/803; 631/80/79/1236; 64; 64/60; 82; 82/80; Aged; Antibodies, Monoclonal - administration & dosage; Apoptosis; Bone cancer; Bone growth; Bone marrow; Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Bone Neoplasms - pathology; Bone Neoplasms - secondary; Bone resorption; Bone tumors; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Care and treatment; Cell adhesion; Cell adhesion & migration; Cell Adhesion - drug effects; Cell Adhesion - genetics; Cell Biology; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell Proliferation - genetics; Colonization; Complications and side effects; Development and progression; Female; Fibronectin; Gene Expression Regulation, Neoplastic - genetics; Genetic aspects; Health aspects; Human Genetics; Humans; Integrins; Integrins - genetics; Internal Medicine; Kaplan-Meier Estimate; Life Sciences; Medicine; Medicine & Public Health; Metastases; Metastasis; Middle Aged; Monoclonal antibodies; Morbidity; Multivariate analysis; Neoplasm Metastasis; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Oncology; Osteoclasts; Osteolysis; Osteolysis - genetics; Patients; Progression-Free Survival; Risk groups; Tumor cells; Tumorigenesis; France
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-01603-6

Bone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients ( n  = 268; p  = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets ( n  = 855, HR = 1.36, p  = 0.018 and n  = 427, HR = 1.62, p  = 0.024). This prognostic value remained significant in multivariate analysis ( p  = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases.