Characterization of the Notch/PKCβ/NF-κB signalling pathway in the tumor microenvironment of chronic lymphocytic leukemia

肿瘤微环境（tumor microenvironment， TME）是肿瘤扩散和发展的重要组成部分。与骨髓和淋巴组织的圆形接触是慢性淋巴细胞白血病（CLL）的标志之一。重要的是，癌细胞的新陈代谢与正常细胞有很大的不同。我们的数据表明，在CLL接触后，骨髓基质细胞（BMSCs）的葡萄糖代谢发生了pkc β依赖的变化。在本研究中，我们希望进一步分析胰岛素对骨髓间充质干细胞精通和缺乏PKCβ代谢的影响，以响应CLL接触。此外，我们还描述了CLL细胞中Wnt信号激活所必需的基质Notch信号的作用。此外，我们的数据表明Notch与骨髓间充质干细胞中的PKCβ/NF-κB信号通路有关。这种相关性将在本提案中使用我们的3D BMSC/白血病模型进行研究。基于Notch、PKCβ、NF-κB与自噬/ EMT调控之间的复杂联系，本课题将在三维白血病/基质模型中分析CLL骨髓生态位中自噬和EMT之间的串扰。

The tumor microenvironment (TME) is an essential component of tumor propagation and progression. The circular contact with the bone marrow and the lymphoid tissues is one of the hallmarks of chronic lymphocytic leukemia (CLL). Importantly, the metabolism of cancer cells differs largely to that of normal cells. Our data demonstrate PKCβ-dependent changes in the glucose metabolism of bone marrow stromal cells (BMSCs) after CLL contact. In this proposal we want to further analyse the effect of insulin to the metabolism of BMSCs proficient and deficient for PKCβ in response to CLL contact. Additionally, we describe a role of the stromal Notch signaling that is required for the activation of Wnt signaling in CLL cells. Moreover, our data indicate a connection of Notch and the PKCβ/NF-κB signaling in BMSCs. This correlation will be investigated in this proposal using our 3D BMSC/leukemia model. Based on the complex links between Notch, PKCβ, NF-κB and the autophagy/ EMT regulation, analysis of the crosstalk between autophagy and EMT in the bone marrow niche of CLL in a 3D leukemia/stroma model will be addressed in this proposal.