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

慢性淋巴细胞白血病肿瘤微环境中Notch/PKCβ/NF-κB信号通路的表征

• 批准号: 388042103
• 负责人: Dr. Gloria Lutzny-Geier
• 金额: --
• 依托单位: Medizinische Klinik 5 -Hämatologie und Internistische Onkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/388042103?language=en
• 关键词: Characterization; Notch; PKC; NF; signalling

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.

肿瘤微环境（TME）是肿瘤增殖和进展的重要组成部分。与骨髓和淋巴组织的循环接触是慢性淋巴细胞白血病（CLL）的标志之一。重要的是，癌细胞的代谢与正常细胞的代谢有很大不同。我们的数据表明，在CLL接触后，骨髓基质细胞（BMSC）的葡萄糖代谢的PKCβ依赖性变化。在本提案中，我们希望进一步分析胰岛素对PKCβ表达丰富和缺乏的BMSC在应对CLL接触时代谢的影响。此外，我们还描述了基质Notch信号传导的作用，这是激活CLL细胞中Wnt信号传导所必需的。此外，我们的数据表明Notch与BMSCs中的PKCβ/NF-κB信号通路有关。在本提案中，将使用我们的3D BMSC/白血病模型研究这种相关性。基于Notch、PKCβ、NF-κB与自噬/ EMT调控之间的复杂联系，本研究将在三维白血病/间质模型中分析CLL骨髓小生境中自噬与EMT之间的串扰。