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

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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.