Dosage-Dependent Hedgehog Signaling in Pancreatic Cancer
胰腺癌中剂量依赖性 Hedgehog 信号转导
基本信息
- 批准号:9328035
- 负责人:
- 金额:$ 37.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-25 至 2020-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAllelesAntibodiesBasal cell carcinomaCDON geneCancer EtiologyCell surfaceCessation of lifeClinicalClinical TrialsCollaborationsDataDevelopmentDiseaseDissectionEmbryonic DevelopmentEnsureErinaceidaeFibroblastsGLI Family ProteinGLI geneGenerationsGeneticGenetic TranscriptionGoalsHomeostasisImpairmentIndividualInjectableKnowledgeLaboratoriesLesionLigandsMaintenanceMalignant NeoplasmsMalignant neoplasm of pancreasMusNatural regenerationNeoplasm MetastasisOrganOutcomePTCH2 genePancreasPathologyPathway interactionsPatternPharmacologyPlayRegulationResearchRhabdomyosarcomaRoleSignal TransductionSurvival RateTestingTissuesTransgenesTumor Cell LineTumor-DerivedUnited StatesWorkdosageeffective therapyexperimental studyhedgehog signal transductioninhibitor/antagonistinsightloss of functionmedulloblastomamouse modelneoplastic cellnew therapeutic targetnovelnovel strategiesnovel therapeutic interventionpancreatic neoplasmpancreatic tumorigenesisparacrinepublic health relevancereceptorsmoothened signaling pathwaytooltumortumor growthtumorigenesis
项目摘要
DESCRIPTION (provided by applicant): Hedgehog (HH) signaling acts throughout embryonic development to ensure proper tissue patterning and organ formation, while in adults HH signaling is vital for tissue maintenance and homeostasis. Aberrant HH pathway activity contributes to numerous developmental diseases and drives the initiation and progression of several cancers, including basal cell carcinoma, rhabdomyosarcoma, and medulloblastoma. More recently, de-regulated HH signaling has been implicated in multiple additional cancers, including pancreatic cancer, where tumor cell-derived HH ligands signal in a paracrine manner to the surrounding microenvironment. In particular, pancreatic cancer is characterized by an extensive HH-responsive fibrotic stroma that promotes tumor growth. However, strikingly little is known about the mechanisms by which HH signaling acts in pancreatic cancer. We propose to address this critical gap in our knowledge through a systematic analysis of the requirement for dosage-dependent HH signaling in pancreatic tumor growth. Through a collaborative effort, the Allen and the Pasca di Magliano laboratories have determined that altering the dosage of HH signaling through targeting of the HH co-receptors GAS1, BOC and CDON differentially regulates pancreatic tumor growth. Surprisingly, pancreatic fibroblasts lacking two of these co-receptors (GAS1 and BOC) have increased tumor-promoting ability compared to wild-type pancreatic fibroblasts when co-injected with tumor cells in mice. In contrast, pancreatic fibroblasts lacking all three co-receptors are unable to promote pancreatic tumor growth. These data suggest that the dosage of HH signaling dramatically affects pancreatic tumor growth. Further, these findings have important clinical implications, and provide an explanation for the negative outcome of recent clinical trials of HH pathway inhibitors in pancreatic cancer. Thus, the central question in this proposal is: how do different levels of HH pathway activity affect pancreatic tumor growth? This proposal continues a unique collaboration between the Allen and Pasca di Magliano labs that combines expertise in HH signaling and pancreatic cancer to test the hypothesis that the level of HH pathway activity is an essential regulator of pancreatic tumor growth. Thus, the objective of this proposal is to define the role of dosage-dependent HH signaling in pancreatic cancer through the dissection of the requirement for 1) HH ligands, 2) HH receptors and 3) downstream HH signal transduction components in pancreatic tumor growth. The expected outcomes of this work include: 1) a comprehensive analysis of the requirement for different levels of tumor-derived HH ligands in pancreatic tumor growth, 2) the elucidation of the relative contributions of cell surface HH receptors and antagonists to stromal promotion of pancreatic cancer, and 3) a determination of the effects of altered downstream HH pathway activity on tumor growth and metastasis. We expect that these results will define the role of HH signaling in pancreatic tumor growth and will provide insight into novel approaches to successfully target the HH pathway in the treatment of pancreatic cancer and other HH-driven pathologies.
描述(由申请人提供):Hedgehog(HH)信号传导在整个胚胎发育过程中发挥作用,以确保适当的组织模式和器官形成,而在成年人中,HH信号传导对组织维持和体内平衡至关重要。异常HH通路活性导致许多发育性疾病,并驱动几种癌症的发生和进展,包括基底细胞癌、横纹肌肉瘤和髓母细胞瘤。最近,去调节的HH信号传导已经涉及多种另外的癌症,包括胰腺癌,其中肿瘤细胞衍生的HH配体以旁分泌方式向周围微环境发出信号。特别是,胰腺癌的特征在于促进肿瘤生长的广泛的HH-响应性纤维化基质。然而,对HH信号在胰腺癌中的作用机制知之甚少。我们建议通过系统分析胰腺肿瘤生长中剂量依赖性HH信号传导的需求来解决我们知识中的这一关键空白。通过合作努力,艾伦和Pasca di Magliano实验室已经确定,通过靶向HH共受体GAS 1、BOC和CDON来改变HH信号传导的剂量可以差异性地调节胰腺肿瘤生长。令人惊讶的是,与野生型胰腺成纤维细胞相比,缺乏这些共受体中的两种(GAS 1和BOC)的胰腺成纤维细胞在与肿瘤细胞共注射到小鼠中时具有增加的肿瘤促进能力。相反,缺乏所有三种共受体的胰腺成纤维细胞不能促进胰腺肿瘤生长。这些数据表明HH信号传导的剂量显著影响胰腺肿瘤生长。此外,这些发现具有重要的临床意义,并为最近HH通路抑制剂在胰腺癌中的临床试验的阴性结果提供了解释。因此,该提案的中心问题是:不同水平的HH途径活性如何影响胰腺肿瘤生长?该提案延续了艾伦和Pasca di Magliano实验室之间的独特合作,结合了HH信号传导和胰腺癌的专业知识,以验证HH通路活性水平是胰腺肿瘤生长的重要调节因子的假设。因此,本提案的目的是通过分析胰腺肿瘤生长中对1)HH配体、2)HH受体和3)下游HH信号转导组分的需求,确定剂量依赖性HH信号传导在胰腺癌中的作用。这项工作的预期成果包括:1)全面分析胰腺肿瘤生长中对不同水平肿瘤源性HH配体的需求,2)阐明细胞表面HH受体和拮抗剂对胰腺癌间质促进的相对贡献,3)确定改变的下游HH途径活性对肿瘤生长和转移的影响。我们期望这些结果将定义HH信号传导在胰腺肿瘤生长中的作用,并将提供对成功靶向HH通路治疗胰腺癌和其他HH驱动的病理的新方法的深入了解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Benjamin Allen其他文献
Benjamin Allen的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Benjamin Allen', 18)}}的其他基金
Investigating GLI transcription factors as regulators of the pancreatic cancer microenvironment
研究 GLI 转录因子作为胰腺癌微环境的调节剂
- 批准号:
10681714 - 财政年份:2023
- 资助金额:
$ 37.82万 - 项目类别:
Kinesin-2 Regulation of GLI Function in Hedgehog Signal Transduction
Kinesin-2 对 Hedgehog 信号转导中 GLI 功能的调节
- 批准号:
9441784 - 财政年份:2016
- 资助金额:
$ 37.82万 - 项目类别:
Kinesin-2 Regulation of GLI Function in Hedgehog Signal Transduction
Kinesin-2 对 Hedgehog 信号转导中 GLI 功能的调节
- 批准号:
9274992 - 财政年份:2016
- 资助金额:
$ 37.82万 - 项目类别:
Dosage-Dependent Hedgehog Signaling in Pancreatic Cancer
胰腺癌中剂量依赖性 Hedgehog 信号转导
- 批准号:
9762017 - 财政年份:2015
- 资助金额:
$ 37.82万 - 项目类别:
Dosage-Dependent Hedgehog Signaling in Pancreatic Cancer
胰腺癌中剂量依赖性 Hedgehog 信号转导
- 批准号:
9150517 - 财政年份:2015
- 资助金额:
$ 37.82万 - 项目类别:
Hedgehog signaling in maintaining taste organ structure and function: basic and clinical studies
Hedgehog信号传导在维持味觉器官结构和功能中的作用:基础和临床研究
- 批准号:
8841584 - 财政年份:2014
- 资助金额:
$ 37.82万 - 项目类别:
Hedgehog signaling in maintaining taste organ structure and function: basic and clinical studies
Hedgehog信号传导在维持味觉器官结构和功能中的作用:基础和临床研究
- 批准号:
9171921 - 财政年份:2014
- 资助金额:
$ 37.82万 - 项目类别:
Novel Hedgehog Receptors As Therapeutic Targets In Pancreatic Cancer
新型 Hedgehog 受体作为胰腺癌的治疗靶点
- 批准号:
8449102 - 财政年份:2012
- 资助金额:
$ 37.82万 - 项目类别:
Novel Hedgehog Receptors As Therapeutic Targets In Pancreatic Cancer
新型 Hedgehog 受体作为胰腺癌的治疗靶点
- 批准号:
8285346 - 财政年份:2012
- 资助金额:
$ 37.82万 - 项目类别:
University of Michigan Postbaccalaureate Research Education Program (UM PREP)
密歇根大学学士后研究教育计划(UM PREP)
- 批准号:
10581633 - 财政年份:2009
- 资助金额:
$ 37.82万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 37.82万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 37.82万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 37.82万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 37.82万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 37.82万 - 项目类别:
Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 37.82万 - 项目类别:
Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
- 批准号:
10065645 - 财政年份:2023
- 资助金额:
$ 37.82万 - 项目类别:
Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 37.82万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 37.82万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 37.82万 - 项目类别:
Grant-in-Aid for Scientific Research (C)