Molecular Dissection of Cytokine Crosstalk in the Tumor Microenvironment

项目摘要 尽管认识到炎症在癌症生物学中的广泛后果，但对肿瘤细胞的机制性影响仍然存在。 肿瘤景观仍然不完全了解。事实上，癌症中的先天和适应性免疫功能可以 是有益的还是有害的，相反的作用突出了我们对如何理解知识的差距。 炎症塑造肿瘤微环境（TME）。该项目将填补这一空白， 通过定义和描述细胞因子如何调节组成的多种细胞类型的功能， 肿瘤微环境我们以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或干性， 与上皮-间充质转化（EMT）有关。此外，这些表型是 通常通过调节分化潜能、细胞-细胞 相互作用和流动性、纤维化和对多种治疗方式的敏感性。目前，该计划以 两大主题。第一个是定义控制细胞因子（I型IFN，IL-10）如何影响细胞增殖的信号传导机制。 17，TGF β）调节（积极和消极）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。第二 这一主题将这些细胞特异性EMT反应与对转移、纤维化和耐药的特异性作用联系起来。 多种治疗策略。我们的主要目标是充分利用我们对细胞因子作用的理解， TME在癌症治疗中的具体改进。应用程序中的三个项目将共同测试 以下总体假设：细胞因子信号具有不同的，有时相互矛盾的机制作用， 通过EMT和癌症干细胞发育的改变来进行癌症进展。这些机制导致 负责持续转移扩散和对多种治疗药物耐药的关键表型特性 方式（化疗，免疫治疗）。该假设将通过以下方式进行检验：（1）定义信号事件 由TGF β、IL-17和/或I型IFN启动， 与TME和癌细胞表型的控制有因果关系，（2）确定这些特异性信号传导如何 途径和基因表达事件是获得治疗抗性的机制 和（3）评价不同细胞类型对肿瘤表型和治疗抗性的贡献， 强调肿瘤细胞的内在机制，免疫细胞浸润和活动，以及基质细胞的控制， 肿瘤通路

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.