Targeting Transglutaminase 2 in cancer cachexia

项目总结 恶病质对许多癌症患者的生存和生活质量有毁灭性的影响，仍然是一个未得到满足的问题。 医疗需要。胰腺癌患者恶病质的发生率最高(~90%)，以及 这些患者中约有三分之一的人体重减轻了10%以上，导致一般情况下 肌肉无力，正常活动受损，最终因呼吸衰竭而死亡。更深一层的 了解导致恶病质复杂代谢缺陷的潜在机制 有了有效的治疗选择，将改善癌症患者肌肉萎缩的管理。 我们最近报道了转录因子Twist1在肌祖细胞中的异位表达 细胞足以引起严重的肌肉萎缩，类似于肌肉恶病质。使用几种遗传小鼠模型 在胰腺导管腺癌(PDAC)中，我们检测到Twist1在癌组织中的高表达 恶病质。尤其重要的是，无论是从遗传上还是从药理学上讲，使肌肉扭曲失活是 足以逆转肌肉恶病质并提高几种癌症恶病质遗传小鼠模型的存活率， 提示Twist1可能是减轻癌症患者肌肉恶病质的靶点。 非常偶然的是，我们发现在癌症恶病质期间，肌肉Twist1高度交联化。我们 获得了强有力的证据，表明这一过程是由交联酶转谷氨酰胺酶2介导的 (TGM2)。特异性TGM2抑制剂处理细胞可完全抑制Twist1诱导的血管内皮生长因子表达 MuRF1和Atrogin1，两种泛素连接酶，在肌肉恶病质过程中推动肌肉蛋白质降解。其他 初步数据表明，Twist1在体内的表达促进了肌肉TGM2的表达。更关键的是， 我们检测到恶病质癌症患者肌肉Twist1和TGM2的表达显著增加 与健康的人相比，证明了我们的发现的临床相关性。 基于这些有趣的发现，我们假设TGM2可能与Twist1合作发挥作用 协调一个前馈网络，在癌症进展过程中启动和维持肌肉恶病质。我们 还假设开发针对TGM2和Twist1的联合治疗策略可能 通过降低每种药物所需的剂量来减轻潜在的药物毒性，并打击 抵抗。这些最重要的假设将在我们的研究提案中得到检验。 具体目的1：探讨TGM2和Twist1在肌肉恶病质发病中的关系 具体目标2：用遗传学方法探索TGM2-Twist1轴在肌肉恶病质中的作用 靶向TGM2和Twist1对肌肉恶病质的治疗价值 我们相信，利用这种新型TGM2/Twist1轴治疗肌肉恶病质的创新方案将达到顶峰 在我们对这种致命的消耗综合征的理解和治疗方面的范式转变。

PROJECT SUMMARY Cachexia has a devastating impact on survival and quality of life of many cancer patients and remains an unmet medical need. Pancreatic cancer patients present with the highest incidence of cachexia (~90%), and approximately one-third of these patients lose more than 10% of their pre-illness weight, leading to general muscle weakness, impairment of normal activities, and eventually death through respiratory failure. A deeper understanding of the underlying mechanisms that lead to the complex metabolic defects of cachexia, coupled with effective treatment options, would improve management of muscle wasting in cancer patients. We have recently reported that ectopic expression of the transcription factor Twist1 in muscle progenitor cells is sufficient to cause severe muscle atrophy akin to muscle cachexia. Using several genetic mouse models of pancreatic ductal adenocarcinoma (PDAC), we detected high Twist1 expression in muscle undergoing cancer cachexia. Of particular importance, inactivating muscle Twist1, either genetically or pharmacological, was sufficient to reverse muscle cachexia and improve survival in several genetic mouse models of cancer cachexia, implicating Twist1 as a possible target for attenuating muscle cachexia in cancer patients. Quite serendipitously, we found that muscle Twist1 was highly crosslinked during cancer cachexia. We obtained strong evidence that this process was mediated by the crosslinking enzyme Transglutaminase 2 (TGM2). Treatment of cells with a specific TGM2 inhibitor completely suppressed Twist1-induced expression of MuRF1 and Atrogin1, two ubiquitin ligases that drive muscle protein degradation during muscle cachexia. Other preliminary data showed that expression of Twist1 in vivo promotes muscle TGM2 expression. More crucially, we detected a marked increase in both muscle Twist1 and TGM2 expression in cachectic cancer patients as compared to healthy individuals, attesting to the clinical relevance of our findings. Based on these intriguing findings, we hypothesize that TGM2 might function in partnership with Twist1 to orchestrate a feed-forward network that initiates and sustains muscle cachexia during cancer progression. We also hypothesize that developing combinatorial therapeutic strategies targeting both TGM2 and Twist1 could mitigate potential drug toxicity by lowering the dose needed for each medicine and combat the development of resistance. These overarching hypotheses will be tested in our research proposal. Specific Aim 1: Investigate the relationship between TGM2 and Twist1 during muscle cachexia Specific Aim 2: Explore the role of the TGM2-Twist1 axis in muscle cachexia using genetic approaches Specific Aim 3: Test the therapeutic value of targeting both TGM2 and Twist1 in muscle cachexia We believe that our innovative proposal to exploit this novel TGM2/Twist1 axis in muscle cachexia will culminate in a paradigm shift in our understanding and therapeutic treatment of this lethal wasting syndrome.