Fibroblast Heterogeneity in Pancreatic Cancer
胰腺癌中成纤维细胞的异质性
基本信息
- 批准号:10467049
- 负责人:
- 金额:$ 78万
- 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:2021-08-10 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAffectAllelesAntigensBiologyCell SurvivalCellsCellular AssayChemoresistanceChromatinClinical ResearchCoculture TechniquesComplementComplexComputational BiologyComputer AnalysisComputing MethodologiesCytometryCytotoxic T-LymphocytesDesmoplasticDevelopmentDiseaseDisease ProgressionDrug Delivery SystemsFibroblastsGenesGenetic TranscriptionHeterogeneityHistologicHumanIL1R1 geneImageImmuneImmunosuppressionImmunotherapyIn SituInflammatoryKPC modelKRAS oncogenesisKRAS2 geneLeadLigandsMachine LearningMalignant NeoplasmsMalignant neoplasm of pancreasMediator of activation proteinMetastatic Neoplasm to the LiverMethodsMitogensModelingMusMutationOrganoidsOutcomePancreatic Ductal AdenocarcinomaParacrine CommunicationPathway interactionsPatientsPharmacologyPharmacotherapyPhenotypePopulationPropertyProteinsRNARegimenRegulatory ElementResearchResistanceResolutionRoleSignal PathwaySignal TransductionSpecimenT-LymphocyteTarget PopulationsTestingTherapeuticTissuesTranslatingTransposaseTumor-infiltrating immune cellsWorkXenograft Modelanalytical methodcancer cellcombinatorialcurative treatmentseffective therapyimmune checkpointimmune checkpoint blockadeimmunoregulationimprovedmacrophagemouse modelmutantnovelnovel therapeutic interventionnovel therapeuticspancreas developmentpancreatic ductal adenocarcinoma modelpancreatic neoplasmparacrinepatient prognosispreclinical studypreventprogenitorrecruitsingle-cell RNA sequencingtherapeutic targettherapy designtooltranscriptomicstransplant modeltumortumor growthtumor progressiontumor-immune system interactions
项目摘要
ABSTRACT
Pancreatic ductal adenocarcinoma (PDA) is characterized by an extensive desmoplastic stroma that represents
a major challenge for its effective treatment and improved survival of patients. We seek to define the composition
and roles of cancer-associated fibroblasts (CAFs), the most abundant cell population in the PDA stroma, as a
potential avenue for the development of new therapeutic strategies. Although CAFs have been historically
considered tumor-promoting components, their ablation in pre-clinical and clinical studies have led to mixed
outcomes, indicating the poorly understood complexity of CAFs. To investigate CAF biology, we previously
established a pancreatic tumor organoid/fibroblast co-culture model. In addition, we performed single cell RNA-
sequencing (scRNA-seq) of murine and human PDA specimens to characterize CAF composition at single-cell
resolution. These analyses have revealed that fibroblasts are heterogeneous and comprised of at least three
distinct subtypes with unique transcriptional and functional features. More so, this heterogeneity emphasizes the
need to design therapies that selectively target the tumor-promoting CAF populations. Although our work has
started to reveal the complex heterogeneity of fibroblasts in primary or metastatic PDA tissues, iterative
developments in scRNA-seq and analysis methods have revealed four additional CAF subtypes in primary and
metastatic PDA. To comprehensively define the CAF repertoire in primary and metastatic PDA, we will
systematically differentiate CAF subtypes and their regulatory elements using scRNA-seq, scATAC-seq,
machine-learning computational methods, and in situ tissue analytic methods that detect RNA and protein
species, such as imaging mass cytometry (Aim 1). We hypothesize that a deeper understanding of the dynamic
CAF states that occurs in primary and metastatic PDA will guide the selection of specific therapeutic regimens.
To complement this analysis, we will identify new CAF subtypes and study their dynamics in a novel murine
model with a reversible mutant Kras allele (Aim 2). Furthermore, we will study CAF-activating pathways by
investigating several genes implicated in stromal activation that were revealed using our recently developed
intraductal transplantation model of PDA (Aim 2). These new mediators appear to have roles in PDA progression,
immunosuppression, and stromal activation, and may represent new PDA therapeutic targets. Finally, we have
demonstrated different immunomodulatory functions of distinct CAF subtypes. We will test combinatorial
strategies to target distinct CAF subtypes in the PDA microenvironment, and study the effect of these strategies
on tumor progression in a murine PDA model (Aim 3). In addition, we will assess the role of macrophage-CAF
crosstalk in promoting and maintaining CAF identify. Overall, this project will clarify the diversity of PDA CAFs
and the role of cancer cells in regulating CAF subtypes. Our results will provide new avenues for CAF-targeting
that we intend to translate towards improved therapies for patients afflicted by this lethal disease.
摘要
胰腺导管腺癌(PDA)的特征是广泛的促纤维增生间质,
其有效治疗和改善患者生存的主要挑战。我们试图定义
以及癌相关成纤维细胞(CAF)(PDA间质中最丰富的细胞群)作为一种细胞因子的作用。
开发新的治疗策略的潜在途径。尽管CAF在历史上
考虑到促肿瘤成分,其在临床前和临床研究中的消融导致了混合
结果,表明对CAF的复杂性知之甚少。为了研究CAF生物学,我们以前
建立胰腺肿瘤类器官/成纤维细胞共培养模型。此外,我们进行了单细胞RNA-
对鼠和人PDA标本进行测序(scRNA-seq),以表征单细胞CAF组成
分辨率这些分析表明,成纤维细胞是异质的,并且由至少三个
具有独特的转录和功能特征的不同亚型。更重要的是,这种异质性强调了
需要设计选择性靶向肿瘤促进CAF人群的治疗方法。虽然我们的工作
开始揭示原发性或转移性PDA组织中成纤维细胞的复杂异质性,
scRNA-seq和分析方法的发展揭示了原发性和继发性CAF中另外四种CAF亚型,
转移性PDA为了全面定义原发性和转移性PDA的CAF谱,我们将
使用scRNA-seq,scATAC-seq,
机器学习计算方法和检测RNA和蛋白质的原位组织分析方法
物种,如成像质谱细胞术(Aim 1)。我们假设,更深入地了解
CAF指出,发生在原发性和转移性PDA将指导具体治疗方案的选择。
为了补充这一分析,我们将确定新的CAF亚型,并在一种新的小鼠模型中研究它们的动力学。
具有可逆突变Kras等位基因的模型(Aim 2)。此外,我们将研究CAF激活途径,
研究涉及基质激活的几个基因,这些基因是使用我们最近开发的
PDA导管内移植模型(目的2)。这些新的介质似乎在PDA进展中起作用,
免疫抑制和基质激活,并可能代表新的PDA治疗靶点。我们终于有
显示了不同CAF亚型的不同免疫调节功能。我们将测试组合
针对PDA微环境中不同CAF亚型的策略,并研究这些策略的效果
在鼠PDA模型中对肿瘤进展的影响(目的3)。此外,我们将评估巨噬细胞-CAF的作用,
串话在促进和维持CAF认同中的作用。总的来说,这个项目将澄清PDA CAFs的多样性
以及癌细胞在调节CAF亚型中的作用。我们的研究结果将为CAF靶向治疗提供新的途径
我们打算将其转化为对这种致命疾病患者的改进疗法。
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)
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David A Tuveson其他文献
Modeling human lung cancer in mice: similarities and shortcomings
在小鼠中模拟人类肺癌:相似性与不足之处
- DOI:
10.1038/sj.onc.1203107 - 发表时间:
1999-09-20 - 期刊:
- 影响因子:7.300
- 作者:
David A Tuveson;Tyler Jacks - 通讯作者:
Tyler Jacks
David A Tuveson的其他文献
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{{ truncateString('David A Tuveson', 18)}}的其他基金
Nrf2 Regulation of Ductal Pancreatic Cancer Etiology and Treatment Response
Nrf2 对导管胰腺癌病因和治疗反应的调节
- 批准号:
10056198 - 财政年份:2016
- 资助金额:
$ 78万 - 项目类别:
(PQA-4) Organoid Omics To Detect And Defeat Ductal Pancreatic Cancer
(PQA-4) 类器官组学检测和战胜导管胰腺癌
- 批准号:
9122093 - 财政年份:2014
- 资助金额:
$ 78万 - 项目类别:
(PQA-4) Organoid Omics To Detect And Defeat Ductal Pancreatic Cancer
(PQA-4) 类器官组学检测和战胜导管胰腺癌
- 批准号:
9336271 - 财政年份:2014
- 资助金额:
$ 78万 - 项目类别:
(PQA-4) Organoid Omics To Detect And Defeat Ductal Pancreatic Cancer
(PQA-4) 类器官组学检测和战胜导管胰腺癌
- 批准号:
8792084 - 财政年份:2014
- 资助金额:
$ 78万 - 项目类别:
(PQA-4) Organoid Omics To Detect And Defeat Ductal Pancreatic Cancer
(PQA-4) 类器官组学检测和战胜导管胰腺癌
- 批准号:
8930940 - 财政年份:2014
- 资助金额:
$ 78万 - 项目类别:
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