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
- 来源:
- 关键词:AXIN1 geneAXIN1 proteinAddressAdverse effectsBiological Response Modifier TherapyCTNNB1 geneCellsClassificationCollaborationsComplementDevelopmentDiseaseEnterobacteria phage P1 Cre recombinaseEventExonsFDA approvedGene ExpressionGenesGenetic VariationGlucoseGlutamate-Ammonia LigaseGlutamineHepatocarcinogenesisHumanImmune checkpoint inhibitorImpairmentIn VitroInjectionsIsotope LabelingLeadLigandsLiverLoxP-flanked alleleMalignant NeoplasmsMalignant neoplasm of liverMetabolicMetabolismMinorModelingMolecularMusMutationOncogenicPathogenesisPathway interactionsPlacebosPlayPorcupinesPre-Clinical ModelPrimary carcinoma of the liver cellsRoleSamplingScaffolding ProteinSignal PathwaySignal TransductionSleeping BeautyTailTankyraseTestingTherapeuticTransposaseUniversitiesUnresectableVeinsbasebeta catenincancer therapygain of functiongain of function mutationhepatocellular carcinoma cell lineinhibitorliver cancer modelloss of functionloss of function mutationmolecular subtypesmolecular targeted therapiesmouse modelmutantoverexpressionprecision medicinereceptorresponsetumor
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
期刊论文数量(0)
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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:
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:
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: