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:
  • 金额:
    $ 16.69万
  • 依托单位:
  • 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

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

项目成果

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Xin Chen其他文献

Xin Chen的其他文献

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{{ truncateString('Xin Chen', 18)}}的其他基金

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
  • 批准号:
    10541171
  • 财政年份:
    2022
  • 资助金额:
    $ 16.69万
  • 项目类别:
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
  • 批准号:
    10574374
  • 财政年份:
    2022
  • 资助金额:
    $ 16.69万
  • 项目类别:
Signaling pathways during hepatocarcinogenesis
肝癌发生过程中的信号通路
  • 批准号:
    10636858
  • 财政年份:
    2022
  • 资助金额:
    $ 16.69万
  • 项目类别:
Signaling pathways during hepatocarcinogenesis
肝癌发生过程中的信号通路
  • 批准号:
    10570081
  • 财政年份:
    2022
  • 资助金额:
    $ 16.69万
  • 项目类别:
Cabozentinib based combination therapy for the treatment of hepatocellular carcinoma
基于卡博替尼的联合疗法治疗肝细胞癌
  • 批准号:
    10117217
  • 财政年份:
    2020
  • 资助金额:
    $ 16.69万
  • 项目类别:
Signaling pathways during hepatocarcinogenesis
肝癌发生过程中的信号通路
  • 批准号:
    9906655
  • 财政年份:
    2020
  • 资助金额:
    $ 16.69万
  • 项目类别:
Role of Cancer-Associated Fibroblasts in Cholangiocarcinoma
癌症相关成纤维细胞在胆管癌中的作用
  • 批准号:
    10166796
  • 财政年份:
    2018
  • 资助金额:
    $ 16.69万
  • 项目类别:
Role of Cancer-Associated Fibroblasts in Cholangiocarcinoma
癌症相关成纤维细胞在胆管癌中的作用
  • 批准号:
    10414782
  • 财政年份:
    2018
  • 资助金额:
    $ 16.69万
  • 项目类别:
Inducible systems for studying liver tumor mainenance in vivo
用于研究肝脏肿瘤体内维持的诱导系统
  • 批准号:
    9457376
  • 财政年份:
    2017
  • 资助金额:
    $ 16.69万
  • 项目类别:
Yap and beta-catenin interactions in liver: Implications in Pathophysiology
Yap 和 β-连环蛋白在肝脏中的相互作用:对病理生理学的影响
  • 批准号:
    9901472
  • 财政年份:
    2016
  • 资助金额:
    $ 16.69万
  • 项目类别:
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