Molecular Dissection of Cytokine Crosstalk in the Tumor Microenvironment

肿瘤微环境中细胞因子串扰的分子解析

基本信息

批准号：
10704227
负责人：
GEORGE ROBERT STARK
金额：
$ 187.78万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-13 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704227
关键词：
Ablation Affect Animal Model Biological Cancer Biology Cell Communication Cell Mobility Cells Chemoresistance Chronic Complex Cytokine Network Pathway Cytokine Signaling Data Development Disease Progression Disease Resistance Dissection Epithelium Equilibrium Evaluation Event Failure Fibroblasts Fibrosis Fostering Gene Expression Genetic Transcription Goals IL17 gene Immune Immune checkpoint inhibitor Immunotherapy Inflammation Inflammatory Interferon Type I Interferon-beta Interferons Knowledge Lead Link MADH3 gene Malignant Neoplasms Mediating Mesenchymal Modality Molecular Neoplasm Metastasis Outcome Pathway interactions Phenotype Phosphorylation Physical shape Population Process Production Property Publishing RNA Binding Recurrent disease Repression Resistance Resistance development Role STAT2 gene STAT3 gene Shapes Signal Pathway Signal Transduction Standardization Stem Cell Development Stimulator of Interferon Genes Sting Injury Stromal Cells Testing Therapeutic Transforming Growth Factor beta Treatment Efficacy Tumor Immunity Work cancer cell cancer cell differentiation cancer stem cell cancer therapy cell type cellular targeting chemotherapy cytokine design immune cell infiltrate immune function improved in vivo insight neoplastic cell novel novel therapeutic intervention novel therapeutics posttranscriptional pre-clinical assessment programs response self-renewal stem stemness therapy design therapy resistant treatment response tumor tumor microenvironment tumor progression tumor-immune system interactions tumorigenesis

项目摘要

PROJECT SUMMARY Despite recognition of the broad consequences of inflammation in cancer biology, the mechanistic impact on the tumor landscape remains incompletely understood. Indeed, innate and adaptive immune functions in cancer can be beneficial or detrimental and the opposing roles highlight the gap of knowledge in our understanding of how inflammation sculpts the tumor microenvironment (TME). This Program Project will address this gap of knowledge by defining and delineating how cytokines modulate the functions of the multiple cell types composing the tumor microenvironment. Our previous work has revealed the potential for these inflammatory cytokines to regulate a spectrum of cancer cell phenotypes, including their self-renewal and cellular hierarchy or stemness, that are associated with the epithelial-mesenchymal transition (EMT). Moreover, these phenotypes are commonly associated with cancer progression through modulation of differentiation potential, cell-cell interactions and mobility, fibrosis, and sensitivity to multiple therapeutic modalities. The program is now centered on two major themes. The first is to define the signaling mechanisms that govern how cytokines (type I IFNs, IL- 17,TGFβ) modulate (both positively and negatively) the EMT process. The cellular targets include stem-like tumor cells as well as the non-tumor derived populations, including fibroblasts and immune cells. The second theme relates these cell-specific EMT responses to specific effects on metastasis, fibrosis, and resistance to multiple therapeutic strategies. Our major goal is to parlay our improved understanding of cytokine effects in the TME into specific improvements in cancer therapy. Collectively the three projects in the application will test the following overarching hypothesis: Cytokine signals have distinct and sometimes conflicting mechanistic roles in cancer progression though alterations in EMT and cancer stem cell development. Such mechanisms lead to critical phenotypic properties responsible for continuous metastatic spread and resistance to multiple therapeutic modalities (chemotherapy, immune therapy). This hypothesis will be tested by (1) defining the signaling events initiated by TGFβ, IL-17, and/or Type I IFNs and the endpoint changes in specific gene expression that are causally linked with control of TME and cancer cell phenotypes, (2) determination of how these specific signaling pathways and gene expression events are mechanistically responsible for acquisition of therapeutic resistance and (3) evaluation of the distinct cell type contributions to tumor phenotypes and therapeutic resistance, with emphasis on tumor cell intrinsic mechanisms, immune cell infiltrates and activities, and stromal cell control of tumor access.

项目概要尽管认识到炎症在癌症生物学中的广泛后果，但其对癌症的机制影响事实上，癌症的先天性和适应性免疫功能仍然不完全清楚。是有益的还是有害的，相反的角色凸显了我们在理解如何进行方面的知识差距炎症塑造肿瘤微环境（TME）该项目将解决这一空白。通过定义和描述细胞因子如何调节多种细胞类型的功能来获取知识我们之前的工作揭示了这些炎症细胞因子的潜力。调节一系列癌细胞表型，包括它们的自我更新和细胞层次结构或干性，此外，这些表型与上皮间质转化（EMT）相关。通常通过调节分化潜能、细胞-细胞与癌症进展相关该计划现在集中于相互作用和活动性、纤维化以及对多种治疗方式的敏感性。第一个主题是定义控制细胞因子（I 型 IFN、IL-）的信号传导机制。 17、TGFβ）调节（正向和负向）EMT 过程，细胞靶点包括干细胞样。肿瘤细胞以及非肿瘤来源的群体，包括成纤维细胞和免疫细胞。主题将这些细胞特异性 EMT 反应与对转移、纤维化和耐药性的具体影响联系起来我们的主要目标是充分利用我们对细胞因子效应的进一步了解。 TME 致力于癌症治疗的具体改进，该应用程序中的三个项目将共同进行测试。以下总体假设：细胞因子信号在以下过程中具有独特且有时相互冲突的机制作用：通过 EMT 和癌症干细胞发育的改变导致癌症进展。导致持续转移扩散和对多种治疗方法产生耐药性的关键表型特性该假设将通过（1）定义信号事件进行检验。由 TGFβ、IL-17 和/或 I 型 IFN 引发，以及特定基因表达的终点变化与 TME 和癌细胞表型的控制存在因果关系，(2) 确定这些特定信号传导如何发挥作用途径和基因表达事件在机械上负责获得治疗耐药性 (3) 评估不同细胞类型对肿瘤表型和治疗耐药性的贡献，强调肿瘤细胞内在机制、免疫细胞浸润和活动以及基质细胞控制肿瘤通路。