Deciphering the role of CDCP1 for priming the bone metastatic niche in prostate cancer

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Prostate cancer (PCa) is one of the leading causes of cancer-related deaths among men in developed countries. Patients with advanced prostate cancer often develop bone metastases, leading to bone pain, skeletal fractures, and increased mortality. The bone marrow niche, with its unique environment, is critical for all major steps of metastasis, including the seeding of disseminated tumor cells in the bone, the survival of microscopic metastases under dormancy, and the eventual outgrowth of overt metastases. Preclinical and clinical data suggest that the non-receptor tyrosine Src is an important signaling molecule involved in bone metastasis. However, the recent clinical trial on Src-inhibitor saracatinib reveled toxicity issues but failed to show benefit for patients with bone metastatic and castration-resistant prostate cancer (mCRPC). Therefore, identifying new factors that promote bone metastasis is central for the improvement of patients’ outcome by more specific targeting. Moreover, the precise interaction between tumor cells and their microenvironment needs to be investigated, and the development of more suitable in vivo models that recapitulate the early steps of bone metastasis are fundamental. The CUB-domain containing protein 1 (CDCP1) is transmembrane glycoprotein that is upregulated in various cancer types and its elevated levels are associated with progressive disease and markedly poorer survival. We recently described an important role of CDCP1 in the progression of prostate cancer. In this study, we showed that CDCP1 protein levels were significantly elevated in human metastatic prostate cancer. Additionally, the transgenic overexpression of CDCP1 in the Pten null background in mice resulted in invasive prostate cancer and the spontaneous development of lung and lymph node metastasis. Now, this proposal aims to dissect the molecular role of CDCP1 in the bone metastasis formation, and to develop novel therapeutic nanobodies that target CDCP1 to treat bone metastasis development and progression. Lastly, we will perform a comprehensive characterization of the CDCP1-driven bone metastatic niche over the course of the disease by using flow cytometric and multiplex immunofluorescence based deep phenotyping approaches. In summary, the results of this project will yield novel mechanistic insights into the role of CDCP1 in bone metastasis development and the shaping its microenvironment, and can delineate novel therapeutic approaches to treat prostate cancer patients affected with bone metastasis.