Role of Cancer-Associated Fibroblasts in Cholangiocarcinoma
癌症相关成纤维细胞在胆管癌中的作用
基本信息
- 批准号:10414782
- 负责人:
- 金额:$ 60.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-06-19 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAffectApoptoticBlocking AntibodiesCell CompartmentationCell DeathCell ProliferationCellsCharacteristicsCholangiocarcinomaClinicalClinical ResearchCoculture TechniquesCollagenCollagen ReceptorsDesmoplasticDevelopmentDrug usageExtracellular MatrixFDA approvedFamilyFibroblastsFibrosisGene ExpressionGenesGoalsGrowthHumanIn VitroIncidenceInjectionsIntegrinsInterruptionIntrahepatic CholangiocarcinomaKnock-outKnockout MiceLightLinkLiverLiver neoplasmsMalignant NeoplasmsMalignant neoplasm of pancreasMeasuresMediatingMediator of activation proteinMusMyofibroblastNatureOutcomePancreasPathway interactionsPharmaceutical PreparationsPharmacologyPlatelet-Derived Growth FactorPrimary Malignant Neoplasm of LiverProtein IsoformsRoleSamplingSignal PathwaySignal TransductionSurvival RateSystemTestingTherapeuticTimeTumor PromotersTumor PromotionTumor-Derivedcancer geneticsconventional therapydiscoidin domain receptor 1discoidin receptorexperimental studygenetic approachin vivoinhibiting antibodyinnovationinterestintrahepaticliver injurymigrationneoplastic cellnew therapeutic targetnintedanibnovelnovel therapeutic interventionrecruitsingle cell sequencingsingle-cell RNA sequencingtooltumortumor microenvironment
项目摘要
Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver tumor with limited therapeutic options and 5-year
survival rates of less than 10%. ICC is characterized by its highly desmoplastic nature, with abundance of cancer-
associated fibroblasts (CAF) and extracellular matrix (ECM). The role of CAF and ECM in ICC remain
controversial due to the paucity of functional in vivo studies. While the majority of ICC in vitro studies support a
cancer-promoting role of CAF, recent studies in endogenously arising pancreatic cancer, a highly desmoplastic
tumor with many similarities to ICC, have shown that CAF restrain cancer growth. Here, we seek to answer the
question whether CAF promote or restrain ICC, using a number of novel and cell-specific tools to manipulate
CAF and tumor cells and their crosstalk in endogenously arising ICC in vivo. We hypothesize that CAF and ECM
provide a niche that promotes ICC growth and survival, and that detailed characterization of ICC-CAF crosstalk
will identify novel therapeutic targets within the tumor microenvironment. In Aim 1, we will determine the role
CAF using novel tools to determine how genetic CAF inhibition or early and late CAF ablation affect ICC growth,
proliferative and anti-apoptotic signaling pathways, and mouse survival. In Aim 2, we will investigate pathways
that mediate the recruitment, proliferation and activation of CAF in ICC focusing on the hypothesis that tumor
cells hijack normal fibrogenic mechanism in the liver via tumor-derived TGFb and PDGF isoforms and TGFb-
activating integrins, resulting in accumulation and activation of CAF. In addition to detailed mechanistic studies
in knockout mice and in vitro co-cultures, we will determine whether pharmacologic inhibition of CAF activation
by FDA-approved drug Nintedanib or integrin-blocking antibodies inhibit ICC growth and prolong mouse survival.
In Aim 3, we will determine pathways through which CAF modulate ICC growth, focusing on the hypothesis that
CAF-derived ECM activates tumor-promoting signals in the tumor cell compartment. To test this hypothesis, we
will investigate ICC development in mice with CAF-specific knockout of Col1a1, or tumor-selective knockout of
collagen-sensing receptor discoidin domain receptor 1 (DDR1). In addition, we will determine whether ECM-
mediated stiffness and subsequent activation of mechanosensitive signaling in tumor cells promote ICC
development. We will measure tumor stiffness, activation of mechanosensitive signaling pathways and DDR1
expression in human CCA samples and correlate these to clinical outcomes. The role of stiffness and DDR1 in
ICC growth and CAF-ICC crosstalk will be investigated in more detail in vitro through modulation of stiffness and
by co-culturing CAF and ICC cells that lack Col1a1 or DDR1, respectively. In summary, the proposed studies
will employ novel tools to answer a long-standing question in the field and may provide a basis for targeting ICC-
CAF crosstalk as novel therapeutic strategy for this devastating malignancy.
肝内胆管癌(ICC)是一种侵袭性肝脏肿瘤,治疗选择有限,5年
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)
Current challenges to underpinning the genetic basis for cholangiocarcinoma.
- DOI:10.1080/17474124.2021.1915128
- 发表时间:2021-05
- 期刊:
- 影响因子:3.9
- 作者:Cigliano A;Chen X;Calvisi DF
- 通讯作者:Calvisi DF
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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:
$ 60.91万 - 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:
$ 60.91万 - 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:
10326862 - 财政年份:2021
- 资助金额:
$ 60.91万 - 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:
$ 60.91万 - 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:
$ 60.91万 - 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:
$ 60.91万 - 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:
$ 60.91万 - 项目类别:
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