Investigation of STAT2 Signaling in the tumor microenvironment
肿瘤微环境中 STAT2 信号传导的研究
基本信息
- 批准号:10661993
- 负责人:
- 金额:$ 7.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAffectAnimal ModelApplications GrantsBiologicalBiopsyCRISPR/Cas technologyCancer RelapseCell CommunicationCell ExtractsCellsChemicalsClinicalCoculture TechniquesColonColon CarcinomaColorectal CancerCommunicationComputer AnalysisConditioned Culture MediaDataData SetDevelopmentDiseaseDisease ProgressionEGF geneEnabling FactorsEpidermal Growth Factor ReceptorExposure toExtracellular MatrixExtracellular Matrix ProteinsFibroblastsGene ExpressionGene Expression ProfileGenesGrowthHumanIn VitroIncidenceIncubatedInterferon Type IInvadedInvestigationKnowledgeMAP Kinase GeneMalignant NeoplasmsMeasuresMediatingMediatorMolecularNF-kappa BNeoplasm MetastasisOncogenicPIK3CG genePhenotypePlatelet-Derived Growth FactorPlayProliferatingProteinsRecurrent Malignant NeoplasmResistanceRoleSTAT2 geneSTAT3 geneSignal PathwaySignal TransductionStat2 proteinStromal CellsSystemTNF geneThe Cancer Genome AtlasTherapeutic InterventionTransforming Growth Factor betaTumor BurdenTumor Cell InvasionTumor PromotionTumorigenicityWomanantitumor effectcancer biomarkerscancer cellcancer recurrencecancer therapychemotherapyclinically relevantcolon cancer patientscolon carcinogenesiscolon tumorigenesisin vivointercellular communicationmenmetastatic colorectalmigrationmortalitymultiplex assayneoplastic cellnovel therapeutic interventionphenotypic biomarkerprognostic indicatorprogramssuccesstargeted treatmenttranscription factortranscriptome sequencingtumortumor growthtumor initiationtumor microenvironmenttumor progressiontumorigenesistumorigenic
项目摘要
SUMMARY
Intercellular communication between tumor cells and stromal cells of which major components are
fibroblasts play a significant role in tumor growth, cancer progression and metastasis. This proposal
aims to investigate the role of STAT2 signaling in the exchange of communication between colorectal
cancer (CRC) cells and stromal cancer-associated fibroblasts (CAFs) in the tumor microenvironment.
Our preliminary show that a clinical correlation between high STAT2 expression and poor survival as
well as a positive correlation between STAT2 and markers of CAFs. Analysis of tumor biopsies of CRC
patients showed elevated STAT2 protein in the tumor and surrounding stroma. Studies in two animal
models of CRC reveal that STAT2 is tumorigenic. RNA-Seq analysis exposed a transcriptional signature
associated with tumor associated fibroblasts. Furthermore, we found that STAT2 facilitates the
proliferation and invasion of tumor cells. In parallel, we found that induction of EGF expression in normal
fibroblasts was poorly induced after incubation with conditioned medium from STAT2 deficient tumor
cells. Given these observations, we postulate that STAT2 mediates the crosstalk between the
tumor and CAFs leading to CRC disease progression. The objective is to: (1) Determine whether
intrinsic tumor STAT2 signaling leads to reprogramming of normal fibroblasts to CAFs to promote tumor
growth and (2) Determine whether STAT2 signaling in normal fibroblasts leads to their conversion to
CAFs to enhance tumor growth. Completion of this study will reveal the importance of STAT2 signaling
in the tumor microenvironment as the communication axis (unidirectional vs. bidirectional) between
tumor cells and CAFs to enhance tumor growth, migration, and invasion.
Significance: Treatment of advanced CRC by combining targeted therapies with chemotherapy has
produced modest success. Delineating the oncogenic role of STAT2 signaling in the tumor
microenvironment may lead to the development of novel therapeutic strategies. If results from our study
reveal that STAT2 plays a dynamic role in the establishment of cell-to-cell communication in the tumor
microenvironment, our findings will support a rationale to inhibit STAT2 signaling as a therapeutic
intervention for the treatment of metastatic CRC.
总结
肿瘤细胞和基质细胞之间的细胞间通讯,其主要成分是
成纤维细胞在肿瘤生长、癌症进展和转移中起重要作用。这项建议
目的是研究STAT 2信号在结直肠和结肠癌之间交流中的作用。
肿瘤微环境中的CRC细胞和间质癌相关成纤维细胞(CAF)。
我们的初步研究表明,STAT 2高表达和低生存率之间的临床相关性,
STAT 2与CAFs标志物呈正相关。结直肠癌活检结果分析
患者的肿瘤和周围间质中的STAT 2蛋白升高。两种动物的研究
CRC模型显示STAT 2是致瘤性的。RNA-Seq分析揭示了一个转录特征
与肿瘤相关的成纤维细胞有关。此外,我们发现STAT 2促进了
肿瘤细胞的增殖和侵袭。与此同时,我们发现正常人表皮生长因子表达的诱导,
在与来自STAT 2缺陷肿瘤的条件培养基孵育后,成纤维细胞诱导较差
细胞考虑到这些观察结果,我们假设STAT 2介导了
肿瘤和CAF导致CRC疾病进展。目的是:(1)确定
内源性肿瘤STAT 2信号传导导致正常成纤维细胞重编程为CAF,
(2)确定正常成纤维细胞中的STAT 2信号传导是否导致它们转化为成纤维细胞。
CAF促进肿瘤生长。这项研究的完成将揭示STAT 2信号传导的重要性。
在肿瘤微环境中作为通信轴(单向与双向),
肿瘤细胞和CAF增强肿瘤生长、迁移和侵袭。
意义:靶向治疗与化疗联合治疗晚期结直肠癌,
取得了一定的成功。描述STAT 2信号在肿瘤中的致癌作用
微环境的变化可能导致新的治疗策略的发展。如果我们的研究结果
揭示了STAT 2在肿瘤细胞间通讯的建立中起着动态作用
微环境,我们的研究结果将支持抑制STAT 2信号传导作为治疗的基本原理。
治疗转移性CRC的干预措施。
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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ANA M GAMERO其他文献
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{{ truncateString('ANA M GAMERO', 18)}}的其他基金
STAT2 Signaling in the Pathogenesis of Psoriasis
银屑病发病机制中的 STAT2 信号转导
- 批准号:
10418798 - 财政年份:2021
- 资助金额:
$ 7.93万 - 项目类别:
STAT2 Signaling in the Pathogenesis of Psoriasis
银屑病发病机制中的 STAT2 信号转导
- 批准号:
10303865 - 财政年份:2021
- 资助金额:
$ 7.93万 - 项目类别:
The Role of STAT2 in Flat Non-Polypoid Colorectal Neoplasia
STAT2 在扁平非息肉样结直肠肿瘤中的作用
- 批准号:
9305364 - 财政年份:2017
- 资助金额:
$ 7.93万 - 项目类别:
Evaluation of STAT2 in a Model of Sporadic Colorectal Cancer
散发性结直肠癌模型中 STAT2 的评估
- 批准号:
8322638 - 财政年份:2011
- 资助金额:
$ 7.93万 - 项目类别:
Evaluation of STAT2 in a Model of Sporadic Colorectal Cancer
散发性结直肠癌模型中 STAT2 的评估
- 批准号:
8203847 - 财政年份:2011
- 资助金额:
$ 7.93万 - 项目类别:
Crosstalk between STAT2 and Bim in type I IFN Signaling
I 型 IFN 信号传导中 STAT2 和 Bim 之间的串扰
- 批准号:
8253486 - 财政年份:2009
- 资助金额:
$ 7.93万 - 项目类别:
Crosstalk between STAT2 and Bim in type I IFN Signaling
I 型 IFN 信号传导中 STAT2 和 Bim 之间的串扰
- 批准号:
7697791 - 财政年份:2009
- 资助金额:
$ 7.93万 - 项目类别:
Crosstalk between STAT2 and Bim in type I IFN Signaling
I 型 IFN 信号传导中 STAT2 和 Bim 之间的串扰
- 批准号:
8073617 - 财政年份:2009
- 资助金额:
$ 7.93万 - 项目类别:
Crosstalk between STAT2 and Bim in type I IFN Signaling
I 型 IFN 信号传导中 STAT2 和 Bim 之间的串扰
- 批准号:
8464654 - 财政年份:2009
- 资助金额:
$ 7.93万 - 项目类别:
A Critical Role for Stat2 in Type 1 Intferon-Induced Apoptosis
Stat2 在 1 型干扰素诱导的细胞凋亡中的关键作用
- 批准号:
7690895 - 财政年份:2008
- 资助金额:
$ 7.93万 - 项目类别:
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