Integration of inflammation and cancer by molecular chaperone

项目摘要 慢性和持续的炎症明确地促进了肿瘤的发生。然而，有很多 肿瘤炎症领域的根本挑战。其中，还没有进行系统的研究。 定量和定性地识别和描述特别致癌的炎症类型。 我们假设致癌性炎症是遗传毒性的，并受关键的先天免疫受体调节。 例如特定细胞类型的Toll样受体(TLRs)(假设1)。此外，尽管 在癌症基因组的广泛研究中，较少的研究涉及蛋白质质量控制在癌症中的作用 炎症和肿瘤的发生。与正常细胞相比，癌细胞有很高的新陈代谢需求 这增加了对加速蛋白质折叠的蛋白质伴侣的需求。因此，我们建议，有 癌症特异的热休克蛋白客户网络，在炎症和癌症中发挥关键作用(假设2)。 分子伴侣gp96是HSP90在内质网中的同源蛋白。它统一表示为 在人类肿瘤中高水平表达，gp96高表达与预后不良相关。有趣的是， 我们发现gp96是TLRs的主要伴侣。我们进一步揭示了gp96的缺失 在Mφ中，S保护小鼠免受结肠炎相关性结肠癌的影响，这与细胞因子水平降低和 对编码β-连环蛋白的CTNNB1的保护作用。我们还生成了特定于细胞类型的gp96 KO 通过删除B细胞、调节性T细胞、肠道上皮细胞、血小板和树突状细胞中的gp96基因。这些 独特的模型使我们能够量化这些免疫细胞亚群对炎症的贡献程度- 相关癌症。此外，我们还证明了gp96在陪伴其他几个基因的过程中扮演着重要的角色。 在肿瘤发生中具有战略重要性的客户，包括整合素、Wnt共受体、Her2、IGF-1和表面 转化生长因子β对接受体LRRC32(GARP)我们的发现表明gp96通过整合 细胞固有的致癌客户网络与炎症(假设3)。我们将首先提出我们的假设 确定TLR主伴蛋白gp96是否在特定细胞类型中调节致癌性炎症 时尚，使用一组独特的基因工具。然后我们将完成癌症的高分辨率地图- 通过遗传、药理和生化手段建立特定的gp96客户网络。 这个美国-中国联合项目(RFA-AI-16-006)的最终目标是同时揭示癌症的内在和癌症- Gp96在肿瘤发生中的外在作用，以指导未来新的癌症治疗方法的发展。

Project Summary Chronic and unrelenting inflammation contributes unequivocally to oncogenesis. However, there are many fundamental challenges in the field of onco-inflammation. Among them, systematic study has not been done to quantitatively and qualitatively identify and characterize the type of inflammations that is particularly oncogenic. We hypothesize that oncogenic inflammation is genotoxic and modulated by key innate immune receptors such as Toll-like receptors (TLRs) in a cell type-specific fashion (Hypothesis 1). In addition, despite the extensive study of the cancer genome, fewer studies have addressed the roles of protein quality control in inflammation and oncogenesis. Cancer cells, as compared to normal cells, have a high metabolic demand which increases the need for protein chaperones that accelerate protein folding. We thus propose that there is a cancer-specific HSP-client network that plays pivotal roles in inflammation and cancer (Hypothesis 2). Molecular chaperone gp96 is a paralogue of HSP90 in the endoplasmic reticulum. It is uniformly expressed at a high level in human cancers, and the high expression of gp96 correlates with worse prognosis. Intriguingly, we discovered that gp96 is an obligated master chaperone for TLRs. We further revealed that deletion of gp96 in Mφs protect mice against colitis-associated colon cancer, which correlates with a reduced cytokine level and protection against mutation of Ctnnb1 encoding β-catenin. We have also generated cell type-specific gp96 KO mice by deleting gp96 in B cells, regulatory T cells, gut epithelial cells, platelets and dendritic cells. These unique models allow us to quantify the extent of contribution by these immune cell subsets to inflammation- associated cancer. In addition, we have shown that gp96 plays essential roles in chaperoning several other strategically important clients in oncogenesis, including integrins, Wnt co-receptor, Her2, IGF-1 and surface TGFβ docking receptor LRRC32 (GARP). Our findings suggest that gp96 drives oncogenesis by integrating cell-intrinsic oncogenic client network with inflammation (Hypothesis 3). We will address our hypotheses by first determining if oncogenic inflammation is modulated by the TLR master chaperone gp96 in a cell type-specific fashion, using a battery of unique genetic tools. We will then complete the high resolution mapping of cancer- specific gp96-client network via genetic, pharmacological and biochemical means. The ultimate goal of this US-China joint project (RFA-AI-16-006) is to uncover both cancer-intrinsic and cancer- extrinsic roles of gp96 in oncogenesis to guide the development of novel cancer therapeutics in the future.