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：
10653134
负责人：
Yasmath Ahmed
金额：
$ 63.75万
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/10653134
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 Colon 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 Lipoprotein Receptor MAP Kinase Gene Maintenance Malignant Neoplasms Mediating Modeling Molecular Molecular Weight Mus Mutation Neoplasm Metastasis Organoids PIK3CG gene Pathway interactions Physiological Predisposition Proliferating 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 beta catenin cancer cell cancer initiation cell motility 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 lipoprotein receptor-related protein 6 multidisciplinary mutant novel 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.

项目摘要通过抑制肿瘤腺瘤性息肉病的抑制Wnt受体激活这项研究的长期目的是研究肿瘤抑制剂腺瘤如何息肉病大肠杆菌（APC）通过调节Wnt接收器抑制Wnt信号转导途径复合物（信号体），并演示如何探索目标APC突变体结直肠癌症（CRC）。 Wnt信号传导对于肠道干细胞维持至关重要，而异常该途径的激活最常通过APC突变失活而发生绝大多数CRC的发展。在Wnt信号传导的经典模型中， APC将破坏Wnt途径Beta-catenin中的关键转录激活因子。但是，我们的最近发布的发现揭示了一个其他全新的功能 - APC阻止了信号体的内在化和随之而来的激活，这是一种新的作用，它是进化的保守。我们表明：1）APC的诱导型损失迅速之后是配体无关的信号体激活； 2）耗竭或抗体介导的LRP6抑制（信号体组件）抑制β-catenin的稳定，Wnt靶基因的转录激活，和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必需的。该项目的目的是在体外使用，Ex Vivo，并在体内方法可以更好地了解APC如何抑制信号体激活在生理条件下，并确定信号基础的异常激活如何 APC在肿瘤中失活的后果。三个具体目的是：1）阐明 APC损失促进CRC细胞中信号体组装的机制； 2）识别APC 突变的CRC细胞最容易受到LRP6失活的影响； 3）测试LRP6失活的效率在体内CRC肿瘤性上。因为APC的分子机制可防止 Wnt信号的异常激活对于我们对有色癌变的理解很重要，这项研究所获得的知识将有助于制定新的治疗策略治疗CRC和其他WNT驱动的癌症。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling.

DOI：
10.1038/s41467-021-25634-z
发表时间：
2021-09-06
期刊：
Nature communications
影响因子：
16.6
作者：
Shen C;Nayak A;Neitzel LR;Adams AA;Silver-Isenstadt M;Sawyer LM;Benchabane H;Wang H;Bunnag N;Li B;Wynn DT;Yang F;Garcia-Contreras M;Williams CH;Dakshanamurthy S;Hong CC;Ayad NG;Capobianco AJ;Ahmed Y;Lee E;Robbins DJ
通讯作者：
Robbins DJ