The role of TRIM proteins in colonization of the bone and bone microenvironment modulation of metastatic prostate cancer.

前列腺癌（PCa）最常见的转移部位是骨，患者的发病率和致死率高。为了找到预防或治疗转移性前列腺癌的新治疗靶点，人们正在努力更好地了解前列腺癌细胞骨转移的分子机制。除了众所周知的癌基因和抑癌基因的遗传改变外，基因转录、翻译后修饰和蛋白质降解调控元件的异常活性是导致前列腺癌细胞转移的主要原因。其中，tripartite motif containing proteins （TRIMs）家族已被确定为驱动转移的细胞过程的关键调节因子，并在不同类型的癌症中具有改变的活性。在我们的初步工作中，我们发现TRIM24在PCa骨转移中高度过表达，并预测预后。此外，TRIM8、TRIM11、TRIM47和TRIM68已被描述在PCa中过表达或影响驱动转移的机制。基于这些数据，我们的总体假设是这些特异性TRIM蛋白在PCa的侵袭性和转移性生态位形成中起着至关重要的作用。为了验证我们的假设，我们将追求三个具体目标。首先，我们将描述TRIMs在PCa组织中的表达和遗传状态，包括原发性肿瘤和转移性肿瘤。使用大型和临床特征良好的队列，我们将我们的分子数据与不同的临床病理参数和患者的生存相关联。其次，利用骨转移性PCa细胞进行体外实验，研究TRIMs的功能作用。我们将探讨转移过程中关键步骤所需的细胞特征是否受到特定TRIMs的影响。对参与这些过程的信号分子的详细分析将有助于得出TRIM介导的PCa转移潜力的潜在分子机制的结论。第三，采用共培养实验研究TRIMs是否影响骨转移性PCa细胞与形成骨微环境的细胞之间的通讯。本项目的研究结果将有助于更好地了解促进前列腺癌骨转移的分子过程。由于转移性前列腺癌的不可治愈性，靶向特定分子，如特定TRIM蛋白，可能是转移性前列腺癌患者的治疗选择。

The most common metastatic site of prostate cancer (PCa) is the bone associated with high morbidity and lethality of patients. With the aim to identify novel therapeutic targets which prevent or treat metastasized PCa, major efforts are being made to better understand the molecular mechanisms enabling bone metastatic transition of PCa cells. Besides well-known genetic alterations of oncogenes and tumor suppressor genes, aberrant activity of regulatory elements for gene transcription, post-translational modification and protein degradation mainly contribute to the metastatic potential of PCa cells. Amongst others, the family of tripartite motif containing proteins (TRIMs) have been identified to be crucial regulators of cellular processes driving metastasis, and to possess altered activity in diverse cancer types. In our preliminary work, we found TRIM24 to be highly overexpressed in PCa bone metastases and to predict outcome. In addition, TRIM8, TRIM11, TRIM47 and TRIM68 have been described be overexpressed in PCa or to influence mechanisms driving metastasis. Based on these data, our overall hypothesis is that these specific TRIM proteins have a crucial role in invasiveness and metastatic niche formation of PCa. To test our hypothesis, we will pursue three specific aims. First, we will characterize the expression and genetic status of TRIMs in PCa tissues including primary tumors as well as metastases. Using large and clinically well-characterized cohorts, we will correlate our molecular data with diverse clinic-pathological parameters and patients’ survival. Second, in-vitro experiments using bone metastatic PCa cells will be conducted to investigate the functional role of TRIMs. We will explore whether cellular features which are required for crucial steps during metastasis are influenced by specific TRIMs. Detailed analysis of signaling molecules involved in these processes will allow conclusions about the underlying molecular mechanisms of TRIM mediated metastatic potential of PCa. Third, co-cultivation experiments will be applied to investigate whether TRIMs influence the communication between bone metastatic PCa cells and cells forming the bone microenvironment. Results of this project will contribute to a better understanding of molecular processes promoting PCa metastasis to the bone. Due to the incurable nature of metastatic PCa to date, targeting specific molecules like specific TRIM proteins might be a therapeutic option for patients suffering from metastatic PCa.