Integration of inflammation and cancer by molecular chaperone

项目摘要 慢性和无情的炎症明确有助于肿瘤的发生。有很多 肿瘤炎症领域的根本挑战。其中，对 定量和定性地鉴定和表征特别是致癌的炎症类型。 我们假设致癌性炎症具有遗传毒性，并受关键的先天免疫受体调节 例如Toll样受体（TLR）以细胞类型特异性方式（假设1）。此外，尽管 尽管对癌症基因组进行了广泛的研究，但很少有研究涉及蛋白质质量控制在癌症中的作用。 炎症和肿瘤发生。与正常细胞相比，癌细胞具有高代谢需求 这增加了对加速蛋白质折叠的蛋白质伴侣的需要。因此，我们建议， 癌症特异性HSP客户端网络，在炎症和癌症中起关键作用（假设2）。 分子伴侣gp 96是内质网中HSP 90的一种伴侣。它统一表示为 在人类癌症中的高水平，并且gp 96的高表达与较差的预后相关。有趣的是， 我们发现gp 96是TLR必需的主分子伴侣。我们进一步揭示了gp 96的缺失， 在Mφ中，保护小鼠免受结肠炎相关结肠癌，这与细胞因子水平降低有关， 针对编码β-连环蛋白的Ctnnb 1突变的保护。我们还产生了细胞类型特异性gp 96 KO 通过删除小鼠B细胞、调节性T细胞、肠上皮细胞、血小板和树突细胞中的gp 96。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，我们已经表明，gp 96在陪伴其他几个细胞中起着重要作用。 在肿瘤发生中具有重要战略意义的客户，包括整合素、Wnt共受体、Her 2、IGF-1和表面 TGFβ对接受体LRRC 32（GARP）。我们的研究结果表明，gp 96通过整合 细胞内在致癌客户网络与炎症（假设3）。我们将首先通过以下方式来解决我们的假设 确定致癌性炎症是否由TLR主伴侣蛋白gp 96在细胞类型特异性 时尚，使用一系列独特的遗传工具。我们将完成癌症的高分辨率绘图- 通过遗传学、药理学和生物化学手段，特异性GP 96-客户端网络。 这个中美联合项目（RFA-AI-16-006）的最终目标是揭示癌症内在和癌症- gp 96在肿瘤发生中的外在作用，以指导未来新型癌症治疗剂的开发。

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.