Inhibition of the Wnt Receptor Complex by the Tumor Suppressor Adenomatous Polyposis Coli

项目摘要 肿瘤抑制剂腺瘤性结肠息肉病对Wnt受体激活的抑制作用 本研究的长期目标是研究肿瘤抑制基因腺瘤性结肠炎是如何在肿瘤细胞中表达的。 大肠息肉病（APC）通过调节Wnt受体来抑制Wnt信号转导通路 复合物（信号体），并证明如何利用它来靶向APC突变体结直肠癌 癌症（CRC）。Wnt信号传导对于肠干细胞的维持是必不可少的，而异常的Wnt信号传导对于肠干细胞的维持是必需的。 该途径的激活，最常通过APC的突变失活发生， 绝大多数CRC的发展。在Wnt信号传导的经典模型中， APC是使Wnt通路中的关键转录激活因子β-连环蛋白不稳定。但我们的 最近发表的研究结果揭示了一个额外的和全新的功能- APC防止 信号体的内化和随后的激活，一个新的作用，是进化 保守的我们已经表明：1）APC的诱导性丢失迅速其次是配体非依赖性 信号体激活; 2）LRP 6（信号体）的消耗或抗体介导的抑制 组分）抑制β-连环蛋白的稳定，Wnt靶基因的转录激活， 和APC突变细胞的增殖;和3）在APC突变细胞中，Wnt受体的内吞作用是 这是Wnt信号异常激活所必需的。这个项目的目标是在体外，离体， 和体内方法，以更好地了解APC如何抑制信号体激活 并确定信号体的异常激活是如何导致 APC在肿瘤中失活的后果。三个具体目标是：1）阐明 APC缺失促进CRC细胞中信号体组装的机制; 2）鉴定APC 最易受LRP 6失活影响的突变CRC细胞;和3）测试LRP 6失活的功效 对CRC体内致瘤性的影响。因为APC阻止细胞凋亡的分子机制 Wnt信号的异常激活对于我们理解结直肠癌发生是重要的， 从这项研究中获得的知识将有助于开发新的治疗策略， 治疗CRC和其他Wnt驱动的癌症。

Project Summary Inhibition of Wnt Receptor Activation by the Tumor Suppressor Adenomatous Polyposis Coli The long-term objective of this study is to investigate how the tumor suppressor Adenomatous polyposis coli (APC) inhibits the Wnt signal transduction pathway by regulating the Wnt receptor complex (signalosome) and to demonstrate how this can be exploited to target APC mutant colorectal cancers (CRCs). Wnt signaling is essential for intestinal stem cell maintenance, whereas aberrant activation of this pathway, which occurs most frequently through mutational inactivation of APC, triggers the development of the vast majority of CRCs. In the classical model for Wnt signaling, the sole role of APC is to destabilize the key transcriptional activator in the Wnt pathway, beta-catenin. However, our recently published findings reveal an additional and entirely new function – APC prevents the internalization and consequent activation of the signalosome, a novel role that is evolutionarily conserved. We have shown that: 1) inducible loss of APC is rapidly followed by ligand-independent signalosome activation; 2) depletion or antibody-mediated inhibition of LRP6 (a signalosome component) inhibits the stabilization of beta-catenin, the transcriptional activation of Wnt target genes, and the proliferation of APC mutant cells; and 3) in APC mutant cells, endocytosis of Wnt receptors is required for the aberrant activation of Wnt signaling. The goal of this project is to use in vitro, ex vivo, and in vivo approaches to gain a better understanding of how APC inhibits signalosome activation under physiological conditions and to determine how aberrant activation of the signalosome underlies the consequences of APC inactivation in tumors. The three specific aims are to: 1) elucidate the mechanism by which APC loss promotes signalosome assembly in CRC cells; 2) identify the APC mutant CRC cells most susceptible to LRP6 inactivation; and 3) test the efficacy of LRP6 inactivation on CRC tumorigenicity in vivo. Because the molecular mechanisms by which APC prevents the aberrant activation of Wnt signaling are important for our understanding of colorectal carcinogenesis, the knowledge gained from this study will aid in the development of new therapeutic strategies for the treatment of CRC and other Wnt-driven cancers.