Molecular Dissection of Cytokine Crosstalk in the Tumor Microenvironment

项目总结 尽管人们认识到炎症在癌症生物学中的广泛后果，但炎症对 肿瘤的图景仍然不完全清楚。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，相反的角色突出了我们对如何理解的知识差距 炎症塑造肿瘤微环境(TME)。该计划项目将解决这一差距 通过定义和描绘细胞因子如何调节多种细胞类型组成的功能来获得知识 肿瘤微环境。我们之前的工作揭示了这些炎性细胞因子潜在地 调节一系列癌细胞的表型，包括它们的自我更新和细胞层级或干性， 与上皮-间充质转化(EMT)相关。此外，这些表型是 通常通过调节分化潜能与癌症进展有关，细胞-细胞 相互作用和机动性、纤维化以及对多种治疗方式的敏感性。该计划现在集中在 关于两个主要主题。第一种是定义控制细胞因子(I型干扰素，IL-1)的信号机制。 17，转化生长因子β)对EMT过程进行(积极和消极的)调节。细胞靶标包括干细胞样的 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 Theme将这些细胞特异性EMT反应与转移、纤维化和对 多种治疗策略。我们的主要目标是利用我们对细胞因子作用的更好的理解 在癌症治疗方面的具体改进。应用程序中的三个项目将共同测试 遵循最重要的假设：细胞因子信号在脑出血中具有不同的、有时相互冲突的机制作用 通过EMT的改变和癌症干细胞的发展，癌症的进展。这种机制导致了 导致持续转移扩散和对多种治疗耐药的关键表型特征 治疗方式(化疗、免疫治疗)。这一假设将通过(1)定义信令事件来检验 由转化生长因子β、IL-17和/或I型IFN和终点启动的特定基因表达的变化 与TME和癌细胞表型的控制有因果关系，(2)这些特定信号如何 通路和基因表达事件在机制上与获得治疗耐药有关 以及(3)评估不同细胞类型对肿瘤表型和治疗耐药性的贡献。 强调肿瘤细胞的内在机制，免疫细胞的渗透和活性，以及基质细胞对肿瘤的控制 肿瘤通道。

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.