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

前列腺癌(PCA)是发达国家男性癌症相关死亡的主要原因之一。晚期前列腺癌患者通常会发生骨转移，导致骨痛、骨骼骨折，并增加死亡率。骨髓生态位具有其独特的环境，对于转移的所有主要步骤都是至关重要的，包括播散的肿瘤细胞在骨骼中的种植，微观转移瘤在休眠状态下的存活，以及最终显性转移瘤的生长。临床前和临床资料表明，非受体酪氨酸Src是参与骨转移的重要信号分子。然而，最近关于Src抑制剂沙拉卡替尼的临床试验揭示了毒性问题，但没有显示出对骨转移和去势抵抗前列腺癌(MCRPC)患者的益处。因此，识别促进骨转移的新因素对于通过更具体的靶向改善患者的预后至关重要。此外，还需要研究肿瘤细胞与其微环境之间的精确相互作用，开发更适合的体内模型来概括骨转移的早期步骤是根本。CUB结构域包含蛋白1(CDCP1)是一种跨膜糖蛋白，在多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有关。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蛋白水平在转移性前列腺癌中显著升高。此外，CDCP1在Pten缺失背景中的转基因过表达导致了小鼠侵袭性前列腺癌以及肺和淋巴转移的自发发展。现在，本研究旨在剖析CDCP1在骨转移形成中的分子作用，并开发以CDCP1为靶点的新型治疗性纳米体来治疗骨转移的发生发展。最后，我们将使用基于流式细胞术和多重免疫荧光的深度表型方法对CDCP1驱动的骨转移生态位在疾病过程中的特征进行全面的表征。综上所述，该项目的结果将对CDCP1在骨转移发生中的作用及其微环境的塑造产生新的机制见解，并可以描绘出治疗前列腺癌骨转移患者的新的治疗方法。

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.