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

前列腺癌是发达国家男性癌症相关死亡的主要原因之一。晚期前列腺癌患者经常发生骨转移，导致骨痛、骨折和死亡率增加。骨髓生态位具有独特的环境，对转移的所有主要步骤都至关重要，包括骨中播散的肿瘤细胞的播种，微观转移瘤在休眠状态下的存活以及显性转移瘤的最终生长。临床前和临床数据表明，非受体酪氨酸Src是参与骨转移的重要信号分子。然而，最近的src抑制剂saracatinib的临床试验显示出毒性问题，但未能显示骨转移和去雄抵抗性前列腺癌（mCRPC）患者的益处。因此，确定促进骨转移的新因素是通过更具体的靶向来改善患者预后的核心。此外，肿瘤细胞与其微环境之间的确切相互作用需要进行研究，开发更合适的体内模型来概括骨转移的早期步骤是基础。含cub结构域蛋白1 （CDCP1）是一种跨膜糖蛋白，在各种癌症类型中表达上调，其水平升高与疾病进展和明显较差的生存率相关。我们最近描述了CDCP1在前列腺癌进展中的重要作用。在这项研究中，我们发现CDCP1蛋白水平在人类转移性前列腺癌中显著升高。此外，在Pten缺失背景下，转基因CDCP1在小鼠体内的过表达可导致侵袭性前列腺癌，并自发发展为肺和淋巴结转移。目前，本研究旨在分析CDCP1在骨转移形成中的分子作用，并开发以CDCP1为靶点的新型治疗纳米体来治疗骨转移的发生和进展。最后，我们将通过流式细胞术和基于多重免疫荧光的深度表型分析方法，对疾病过程中cdcp1驱动的骨转移生态位进行全面表征。综上所述，本项目的结果将为CDCP1在骨转移发展及其微环境塑造中的作用提供新的机制见解，并为治疗伴有骨转移的前列腺癌患者提供新的治疗方法。

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.