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：
10541171
负责人：
Xin Chen
金额：
$ 48.04万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10541171
关键词：
AXIN1 gene AXIN1 protein Address Adverse effects Biological CTNNB1 gene Cells Classification Collaborations Complement Development Disease Disparate 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 Productivity Role Sampling Scaffolding Protein Signal Pathway Signal Transduction Sleeping Beauty Tail Tankyrase Testing Therapeutic Transposase Universities Unresectable Veins 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.

抽象的肝细胞癌（HCC）是一种致命的恶性肿瘤，治疗方案有限，并且缺乏分子 - 靶向疗法。 Wnt/β-catenin级联激活的激活已显示在HCC期间起主要作用发病。 CTNNB1的突变，编码β-catenin的基因，干扰其降解导致它的功能获得（GOF）和激活，并在所有HCC的20-35％中实施。互斥的群体大约8％的HCC是AXIN1中具有功能丧失（LOF）突变的HCC，该突变是编码的对于脚手架蛋白AXIN1，对于β-catenin降解至关重要。我们以前的研究还表明β- 仅Catenin激活不足以用于HCC的开发。基于CTNNB1的同时存在约11％的人hcc中的突变和C-MET激活，AXIN1和C-中LOF突变的存在在约4％的人类HCC中，满足了激活，我们建立了两个鼠HCC模型，C-Met/β-catenin和 C-MET/SGAXIN1，使用睡美人的转座子/转座酶和流体动力学尾静脉注射（SB-HDTVI）。这些模型基于基因表达研究概括了各自的人类HCC子集。有趣的是，使用这些鼠标模型和人类HCC样品，我们发现AXIN1 LOF突变体HCC没有显示典型肝特异性β-catenin靶基因的激活，例如谷氨酰胺合成酶（GS）和TBX3，在CTNNB1突变的HCC中证明了这一点。相比之下，河马级联在LOF突变中被灭活 AXIN1突变体，但不在CTNNB1突变的HCC中。基于上述观察，我们的总体假设是尽管β-catenin是常见的下游效应子，但CTNNB1和AXIN1中的突变导致 HCC的独特分子亚型和这两个类别的肿瘤发展需要独特的参与信号通路。我们提出以下三个特定旨在解决我们高度相关假设的特定旨在。在 AIM 1，我们计划定义C-MET/SGAXIN1需要Wnt/β-catenin的配体依赖性激活诱导小鼠的HCC形成。在AIM 2中，我们将调查GS依赖性和独立的代谢以及在鼠标HCC开发中发出信号级联。在AIM 3中，我们将表征 CTNNB1 GOF和AXIN1 LOF突变HCC中的河马级联。总之，我们的研究将阐明独特的由于两种不同的机制引起的β-catenin激活引起的信号传导途径，以及我们如何有效地基于遗传变异靶向这些肿瘤。该提案代表了持续的产品合作在UCSF的Xin Chen博士和匹兹堡大学的Paul Monga博士之间。结果可能铺平 HCC中的精密医学方法。