CARD9调控肺癌肿瘤微环境改变与肿瘤发生的分子机制研究

Tumor development and metastasis rely on tumor microenvironment. Immune cells, including tumor-associated macrophages (TAM) and Myeloid-derived suppressor cells (MDSC), play vital role in the tumor microenvironment, which crosstalk with tumor cells, to influence tumor growth. The development and function of TAM, together with MDSC, depend on the activation of NF-κB signal pathway; however, the exact mechanism needs to be examined. CARD9 is necessary for the activation of NF-κB. We found that CARD9 knockout bone marrow-derived macrophages have defect to differentiate into M2-like macrophage, and transplantation tumor growth in CARD9 knockout mice is much slower than that in wildtype mice. .This research will focus on the molecular mechanisms how CARD9 regulate the lung tumor growth and its tumor microenvironment. We will examine how CARD9 influence the development and function of tumor-associated macrophage together with MDSC. By using transplant tumor model and spontaneous tumor model, together with CARD9/Bcl10/Malt1 knockout mice, we will study how CARD9 and its binding partner regulate the lung tumor growth from three different levels which including molecular, cells and in vivo. This research will help to elucidate the role of CARD9-dependent NF-κB signal pathway in controlling tumor growth and tumor microenvironment. More importantly, this will shed light on finding the effective tumor biological therapy to treat cancer.

肿瘤微环境与肿瘤的发生发展密切相关，以肿瘤相关巨噬细胞和髓样抑制性细胞为代表的免疫细胞在肿瘤微环境中发挥关键作用，与肿瘤细胞相互作用影响肿瘤进程。肿瘤相关巨噬细胞和髓样抑制性细胞的分化需要NF-κB信号通路的活化，但其具体分子机制函待进一步阐明。CARD9在NF-κB激活过程中至关重要。我们前期研究发现，CARD9缺失会造成肿瘤相关巨噬细胞的分化缺陷，CARD9敲除小鼠移植肺癌肿瘤发生率降低。.本项目拟集中研究CARD9对肺癌肿瘤微环境的改变及肺癌发生发展的调控机制。深入分析CARD9影响肿瘤相关巨噬细胞和髓样抑制性细胞分化及行使功能的分子机制；采用移植瘤模型和原发小鼠肺癌模型，结合基因敲除小鼠，从分子、细胞到活体各个层面探讨CARD9对肿瘤微环境改变及肿瘤发生的调控。本项目将有助于阐明CARD9依赖的NF-κB信号通路在肿瘤发生中的作用，进而为寻找有效的肿瘤生物治疗方案提供新思路。

肿瘤微环境与肿瘤的发生发展密切相关，NF-κB相关的炎症信号通路在肿瘤微环境中发挥关键作用。CARD家族成员在NF-κB激活过程中至关重要，本项目集中研究CARD9对肺癌肿瘤微环境的改变及肺癌发生发展的调控机制。我们发现在移植肺癌肿瘤以及EGFR和K-Ras突变引起的两种自发肿瘤模型中CARD9敲除小鼠肿瘤发生率都显著降低，其具体机制为CARD9缺失会造成肿瘤相关巨噬细胞的分化缺陷，最终影响肿瘤发生。本项目将有助于阐明CARD9依赖的NF-κB信号通路在肿瘤发生中的作用，进而为寻找有效的肿瘤生物治疗方案提供新思路。.通过此项目支持，已发表了基金标注的4篇高水平学术论文，包括1篇Nature Medicine、1篇Protein&Cell、1篇Journal of Immunology和1篇PLoS Pathogen，其中3篇文章负责人为通讯作者。培养了2名博士毕业生和1名博士后出站。.