Mechanism and Therapeutic Targeting of TRIM29-mediated Invasion in Bladder Cancer

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Over 17,000 will die from bladder cancer in the U.S. this year. While most patients with noninvasive tumors are cured, most patients with muscle-invasive disease will develop metastases and die. Therefore, understanding and targeting the molecular driver(s) which facilitate this invasive switch is essential to improve patient outcomes. TRIM29 is a critical driver of bladder cancer initiation, invasion and therapeutic resistance in human tumors and mouse models. TRIM29 promotes tumor formation by regulating protein interactions that govern beta-catenin and miRNA activity. TRIM29 impacts therapeutic resistance by regulating ubiquitination of DNA repair and innate immune pathways. The specific mechanism by which TRIM29 drives invasive progression remains poorly understood. Rationale: Emerging evidence from our lab has identified a novel function of TRIM29 in the regulation of intermediate filaments, focal adhesion and FAK/Src signaling. However, we do not yet understand how this TRIM29-focal adhesion axis is regulated, how it participates in progression from non- invasive to invasive cancers in vivo or how it coordinates with previously identified mechanisms to promote invasive progression. This is a critical gap in knowledge because without a clear understanding of these events, we are unable to develop therapeutic strategies to target this pathway and prevent progression to the lethal invasive form of bladder cancer. The specific objective of this proposal is to identify the role of this novel TRIM29-focal adhesion axis in invasive progression and to use this knowledge to develop therapeutic strategies to block invasive progression in high-risk TRIM29+ tumors. The central hypothesis is that TRIM29 drives progression from noninvasive to lethal invasive bladder cancer by driving intermediate filament and focal adhesion formation, and activation of FAK/Src signaling in invasive cells. This hypothesis will be tested in the following specific aims: 1) To conduct detailed structure-function analysis of the TRIM29 interaction with intermediate filaments, the focal adhesion complex, and FAK/Src signaling during invasion. 2) To determine the requirement for TRIM29, KRT14, and focal adhesion proteins during bladder cancer initiation and invasive progression. 3) To evaluate novel therapeutic strategies to block TRIM29-mediated invasion in bladder cancer. Aim 1 will utilize live cell imaging, 3D and animal models of invasion. Aim 2 will leverage unique GEMM of bladder cancer to dissect the essential functions of TRIM29 in vivo. Aim 3 will use our multiple models to identify therapeutic strategies to target TRIM29-mediated invasion. This research is conceptually innovative in the characterization of a novel TRIM29-focal adhesion pathway of invasive progression and technically innovative in the development of novel bladder cancer murine models, advanced 3D tumor invasion assays and novel therapeutic targeting strategies. The proposed research is significant because description of the mechanism of TRIM29-mediated invasive progression will allow identification of novel therapeutic strategies to block development of lethal invasive progression in bladder cancer.