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Investigating multifactorial beta-catenin activation in hepatocellular cancers

研究肝细胞癌中的多因素 β-连环蛋白激活

基本信息

批准号：
10326862
负责人：
Xin Chen
金额：
$ 16.69万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-07 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326862
关键词：
AXIN1 gene AXIN1 protein Address Adverse effects Biological Response Modifier Therapy CTNNB1 gene Cells Classification Collaborations Complement Development Disease Enterobacteria phage P1 Cre recombinase Event Exons FDA approved Gene Expression Genes Genetic Variation Glucose Glutamate-Ammonia Ligase Glutamine Hepatocarcinogenesis Human Immune checkpoint inhibitor Impairment In Vitro Injections Isotope Labeling Lead Ligands Liver LoxP-flanked allele Malignant Neoplasms Malignant neoplasm of liver Metabolic Metabolism Minor Modeling Molecular Mus Mutation Oncogenic Pathogenesis Pathway interactions Placebos Play Porcupines Pre-Clinical Model Primary carcinoma of the liver cells Role Sampling Scaffolding Protein Signal Pathway Signal Transduction Sleeping Beauty Tail Tankyrase Testing Therapeutic Transposase Universities Unresectable Veins base beta catenin cancer therapy gain of function gain of function mutation hepatocellular carcinoma cell line inhibitor liver cancer model loss of function loss of function mutation molecular subtypes molecular targeted therapies mouse model mutant overexpression precision medicine receptor response tumor

项目摘要

Abstract Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options, and lacks molecular- targeted therapies. Activation of Wnt/β-catenin cascade has been shown to play a major role during HCC pathogenesis. Mutations in CTNNB1, the gene encoding for β-catenin, interfere with its degradation leading to its gain-of function (GOF) and activation, and are implicated in 20-35% of all HCCs. A mutually exclusive group of additional around 8% of HCCs is the one with the loss-of-function (LOF) mutations in AXIN1, which encodes for a scaffolding protein AXIN1, essential for β-catenin degradation. Our previous studies also showed that β- catenin activation alone is insufficient for HCC development. Based on the concomitant presence of CTNNB1 mutations and c-MET activation in ~11% of human HCC, and the presence of LOF mutations in AXIN1 and c- MET activation together in ~4% of human HCC, we established two murine HCC models, c-Met/β-catenin and c-Met/sgAxin1, using sleeping beauty transposon/transposase and hydrodynamic tail vein injection (SB-HDTVI). These models recapitulate the respective human HCC subsets based on gene expression studies. Intriguingly, using these mouse models and human HCC samples, we discovered that AXIN1 LOF mutant HCC does not show activation of canonical liver-specific β-catenin target genes such as glutamine synthetase (Gs) and Tbx3, which was evident in CTNNB1-mutant HCCs. In contrast, Hippo cascade is inactivated in LOF mutations in AXIN1 mutant, but not in CTNNB1-mutant HCCs. Based on the above observations, our overarching hypothesis is that despite β-catenin being the common downstream effector, mutations in CTNNB1 and AXIN1 lead to distinct molecular subtypes of HCC, and tumor development in these two classes requires participation of distinct signaling pathways. We propose the following three specific aims to address our highly relevant hypothesis. In Aim 1, we plan to define whether ligand dependent activation of Wnt/β-catenin is required for c-Met/sgAxin1 induced HCC formation in mice. In Aim 2, we will investigate Gs dependent and independent metabolic and signaling cascades in mouse HCC development. And in Aim 3, we will characterize the functional contribution of Hippo cascade in Ctnnb1 GOF and Axin1 LOF mutant HCCs. Altogether, our studies will elucidate the distinct signaling pathways induced by β-catenin activation due to two distinct mechanisms, and how we may effectively target these tumors based on genetic variations. The proposal represents an ongoing & productive collaboration between Dr. Xin Chen from UCSF and Dr. Paul Monga from University of Pittsburgh. The results may pave a way for precision medicine in HCC.

摘要