Therapeutic targeting of CD146/MCAM reduces bone metastasis in prostate cancer

Eugenio Zoni, Letizia Astrologo, Charlotte K. Y. Ng, Salvatore Piscuoglio, Janine Melsen, Joel Grosjean, Irena Klima, Lanpeng Chen, Ewa B. Snaar-Jagalska, Kenneth Flanagan, Gabri van der Pluijm, Peter Kloen, Marco G. Cecchini, Marianna Kruithof de Julio, George N. Thalmann

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Prostate Cancer is the most common cancer and the second leading cause of cancer-related death in males. When prostate cancer acquires castration resistance, incurable metastases, primarily in the bone, occur. The aim of this study is to test the applicability of targeting melanoma cell adhesion molecule (MCAM; CD146) with a mAb for the treatment of lytic prostate cancer bone metastasis. We evaluated the effect of targeting MCAM using in vivo preclinical bone metastasis models and an in vitro bone niche coculture system. We utilized FACS, cell proliferation assays, and gene expression profiling to study the phenotype and function of MCAM knockdown in vitro and in vivo. To demonstrate the impact of MCAM targeting and therapeutic applicability, we employed an anti-MCAM mAb in vivo. MCAM is elevated in prostate cancer metastases resistant to androgen ablation. Treatment with DHT showed MCAM upregulation upon castration. We investigated the function of MCAM in a direct coculture model of human prostate cancer cells with human osteoblasts and found that there is a reduced influence of human osteoblasts on human prostate cancer cells in which MCAM has been knocked down. Furthermore, we observed a strongly reduced formation of osteolytic lesions upon bone inoculation of MCAM-depleted human prostate cancer cells in animal model of prostate cancer bone metastasis. This phenotype is supported by RNA sequencing (RNA-seq) analysis. Importantly, in vivo administration of an anti-MCAM human mAb reduced the tumor growth and lytic lesions. These results highlight the functional role for MCAM in the development of lytic bone metastasis and suggest that MCAM is a potential therapeutic target in prostate cancer bone metastasis. Implications: This study highlights the functional application of an anti-MCAM mAb to target prostate cancer bone metastasis.
Original languageEnglish
Pages (from-to)1049-1062
JournalMolecular Cancer Research
Volume17
Issue number5
DOIs
Publication statusPublished - 1 May 2019
Externally publishedYes

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