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

抑癌基因腺瘤性息肉病大肠杆菌对 Wnt 受体复合物的抑制

基本信息

批准号：
10217057
负责人：
Yasmath Ahmed
金额：
$ 65.05万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10217057
关键词：
APC gene APC mutation APC2 gene Antibodies Apoptosis Attenuated Binding Biochemistry Cancer Etiology Cancer Model Cell Maintenance Cell Proliferation Cells Cessation of life Clathrin Clinical Colorectal Colorectal Cancer Complex Critical Pathways Development Drosophila genus Endocytosis Genes Genetic Genetic Engineering Goals Growth Human Human Engineering In Vitro Intestines Knowledge LDL-Receptor Related Protein 1 Left Ligands MAP Kinase Gene Maintenance Malignant Neoplasms Mediating Modeling Molecular Molecular Weight Mus Mutation Neoplasm Metastasis Organoids Pathway interactions Physiological Proteins Proteolysis Proteomics Publishing Receptor Activation Role Screening procedure Series Signal Transduction Signal Transduction Pathway Sucrose TP53 gene Testing Therapeutic Transcription Coactivator Transcriptional Activation Transforming Growth Factor beta Translating Tumor Suppressor Proteins Tumorigenicity United States WNT Signaling Pathway Xenograft procedure base beta catenin cancer cell cell type colon cancer patients colon carcinogenesis colorectal cancer treatment cost effective density driver mutation druggable target efficacy testing enhancer-binding protein AP-2 in vivo inhibitor/antagonist lipoprotein receptor-related protein 6 multidisciplinary mutant novel novel strategies novel therapeutic intervention paralogous gene patient derived xenograft model prevent receptor stem cells tumor tumor progression

项目摘要

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.

项目概要抑癌基因腺瘤性息肉病大肠杆菌对 Wnt 受体激活的抑制本研究的长期目标是研究肿瘤抑制因子腺瘤如何大肠杆菌（APC）通过调节 Wnt 受体抑制 Wnt 信号转导通路复合物（信号体）并展示如何利用它来靶向 APC 突变结直肠癌症（CRC）。 Wnt 信号对于肠道干细胞的维持至关重要，而异常的该途径的激活最常通过 APC 突变失活而发生，触发绝大多数 CRC 的开发。在 Wnt 信号传导的经典模型中，唯一的作用是 APC 的作用是破坏 Wnt 通路中关键转录激活因子 β-catenin 的稳定性。然而，我们的最近发表的研究结果揭示了一个额外的全新功能——APC 可以防止信号体的内化和随后的激活，这是进化上的一个新角色保守的。我们已经证明：1）APC 的诱导性丢失很快就会出现配体依赖性信号体激活； 2) LRP6（一种信号体）的耗竭或抗体介导的抑制成分）抑制 β-连环蛋白的稳定、Wnt 靶基因的转录激活，以及APC突变细胞的增殖； 3) 在APC突变细胞中，Wnt受体的内吞作用是 Wnt 信号传导异常激活所需的。该项目的目标是利用体外、离体、和体内方法，以更好地了解 APC 如何抑制信号体激活在生理条件下并确定信号体的异常激活是如何发生的肿瘤中 APC 失活的后果。这三个具体目标是：1）阐明 APC 丢失促进 CRC 细胞中信号小体组装的机制； 2) 识别APC 突变型 CRC 细胞最容易受到 LRP6 失活的影响； 3)测试LRP6失活的功效 CRC 体内致瘤性。因为 APC 预防的分子机制 Wnt 信号传导的异常激活对于我们理解结直肠癌发生非常重要，从这项研究中获得的知识将有助于制定新的治疗策略 CRC 和其他 Wnt 驱动的癌症的治疗。