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

今年，美国将有超过17000人死于膀胱癌。虽然大多数非侵袭性肿瘤患者 一旦治愈，大多数肌肉侵袭性疾病的患者都会发生转移并死亡。因此，理解 而靶向促进这种侵入性开关的分子驱动因素(S)对于改善患者是必不可少的 结果。TRIM29是人类膀胱癌发生、侵袭和治疗耐药的关键驱动因素 肿瘤和小鼠模型。TRIM29通过调节调控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泛素化影响药物耐药性 修复和先天免疫途径。TRIM29驱动侵袭性进展的具体机制 人们对此仍然知之甚少。理论基础：来自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、焦点黏附和FAK/Src信号转导中起重要作用。然而，我们并没有 但了解TRIM29焦点粘附轴是如何调节的，它如何参与从非 体内对浸润性癌症的侵袭或它如何与先前已知的机制协调以促进 侵袭性进展。这是知识上的一个关键差距，因为如果不清楚地了解这些 事件，我们无法制定治疗策略，以针对这一途径，并防止进展到 致命的浸润性膀胱癌。这项提议的具体目标是确定这部小说的角色 TRIM29-侵袭性进展中的焦点粘连轴并利用这一知识开发治疗方法 阻止高危TRIM29肿瘤侵袭性进展的策略。中心假设是TRIM29 通过驱动中间丝推动非侵袭性膀胱癌向致命性浸润性膀胱癌的进展 侵袭细胞中FAK/Src信号通路的激活和局部黏附的形成。这一假说将 测试的具体目标如下：1)对TRIM29进行详细的结构-功能分析 侵袭过程中与中间丝、焦点黏附复合体和FAK/Src信号的相互作用。2) 确定膀胱癌发生过程中对TRIM29、KRT14和粘着斑蛋白的需求 和侵袭性进展。3)评估阻断TRIM29介导的侵袭的新的治疗策略。 膀胱癌。AIM 1将利用活细胞成像、3D和动物入侵模型。AIM 2将利用 独特的膀胱癌GEMM，剖析TRIM29在体内的基本功能。Aim 3将使用我们的 多个模型以确定针对TRIM29介导的侵袭的治疗策略。这项研究是 一种新的侵袭性TRIM29-焦点黏附途径的概念创新 新型膀胱癌小鼠模型的研究进展和技术创新 三维肿瘤侵袭分析和新的治疗靶向策略。这项拟议的研究具有重要意义 因为对TRIM29介导的侵袭性进展机制的描述将使我们能够识别 阻止膀胱癌致命侵袭性进展的新治疗策略。

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.