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

今年美国将有超过17,000人死于膀胱癌。虽然大多数非侵袭性肿瘤患者 大多数肌肉浸润性疾病患者在治愈后会发生转移并死亡。因此了解 并且靶向促进这种侵入性转换的分子驱动器对于改善患者 成果。TRIM29是人类膀胱癌发生、侵袭和治疗抗性的关键驱动因素 肿瘤和小鼠模型。TRIM29通过调节蛋白质相互作用促进肿瘤形成， β-连环蛋白和miRNA活性。TRIM29通过调节DNA的泛素化影响治疗抗性 修复和先天免疫途径。TRIM29驱动侵袭性进展的具体机制 仍然知之甚少。理由：我们实验室的新证据已经确定了一种新的功能， TRIM29在调节中间丝、粘着斑和FAK/Src信号中的作用但我们不 然而，了解TRIM29-粘着斑轴是如何调节的，它如何参与从非粘着斑到粘着斑的进展， 在体内的侵袭性到侵袭性癌症或它如何与先前确定的机制协调，以促进 侵袭性进展。这是一个关键的知识差距，因为没有对这些问题的清晰理解， 然而，我们无法开发治疗策略来靶向这一途径并防止进展到 致命的侵袭性膀胱癌这一建议的具体目标是确定这部小说的作用 TRIM29-侵袭性进展中的粘着斑轴，并利用这一知识开发治疗 阻断高风险TRIM29+肿瘤侵袭性进展的策略。核心假设是TRIM29 通过驱动中间丝，推动非侵入性膀胱癌发展为致命的侵入性膀胱癌 和粘着斑形成，以及在侵袭性细胞中FAK/Src信号传导的激活。这一假设将 具体测试目标如下：1）对TRIM29进行详细的结构-功能分析 与中间丝的相互作用，粘着斑复合物，和FAK/Src信号在入侵。（二） 确定膀胱癌发生过程中对TRIM29、KRT14和黏着斑蛋白的需求 和侵入性进展。3)评估阻断TRIM 29介导的侵袭的新的治疗策略， 膀胱癌目标1将利用活细胞成像，3D和动物模型的入侵。Aim 2将利用 膀胱癌的独特GEMM来剖析TRIM29在体内的基本功能。Aim 3将使用我们的 多个模型来鉴定靶向TRIM 29介导的侵袭的治疗策略。本研究是 在概念上创新的一种新的TRIM29-局灶性粘附途径的表征侵袭性 在开发新型膀胱癌小鼠模型方面取得了进展和技术创新， 3D肿瘤侵袭测定和新的治疗靶向策略。所提出的研究是有意义的 因为描述TRIM 29介导的侵袭性进展的机制将允许鉴定 新的治疗策略，以阻止膀胱癌中致命的侵袭性进展的发展。

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.