Lyn kinase as a key regulator in the microenvironmental niche of B lymphoid tumors

Lyn 激酶作为 B 淋巴肿瘤微环境中的关键调节因子

• 批准号: 436315573
• 负责人: Professor Dr. Michael Hallek
• 金额: --
• 依托单位: Klinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/436315573?language=en
• 关键词: Lyn; kinase; key; regulator; microenvironmental

Targeting B cell receptor (BCR)-associated kinases by small molecule kinase inhibitors has generated tremendous advances of the therapy of B lymphoid malignancies such as chronic lymphocytic leukemia (CLL) (Hallek et al., Lancet 2018). Following the introduction of these inhibitors in routine therapy, compelling evidence has emerged showing that their efficacy does not only rely on the inhibition of B cell-autonomous functions. Instead, the mechanism of action of these inhibitors can be explained to a large extent by the modulation of distinct cell types within the lymphoid tumor microenvironment (TME) (Nguyen, Niesen, Hallek, Leukemia 2019).Recently, we have discovered an unexpected, potent functional role of Lyn kinase, a central signaling component of the BCR, for the creation of a pro-malignant leukemia microenvironment (Nguyen et al., Cancer Cell 2016). Particularly, we observed that the presence of Lyn kinase is required to maintain the leukemia supporting capacity of both hematopoietic and non-hematopoietic cells. Moreover, preliminary data of our laboratory suggest that Lyn-deficiency leads to profound proteomic changes in macrophages and fibroblasts in the TME. The proteomic profiling revealed little overlap of Lyn-induced changes in the two cell types, suggesting that Lyn activates distinct, cell-type specific functional pathways in leukemia-associated macrophages and fibroblasts. The central hypothesis of this project is that non-receptor tyrosine kinases such as Lyn function as central modulators of the pro-neoplastic microenvironment for B cell lymphoma. Therefore, an improved mechanistic understanding of the function of these kinases in the lymphoid TME will be useful to design improved anti-lymphoma therapies. In the first aim, we will validate the cell type-specific modulation of novel targets including transcriptional factors within the regulatory network of Lyn kinase in different TME cells. In parallel, we will explore the potential role of Lyn in fibroblast activation and induction of a cancer-promoting phenotype. In the second aim, we will determine the structural signaling domains responsible for the TME action of Lyn using diverse in vitro and in vivo genetic tools. In the third aim, we will employ a high-content, functional arrayed CRISPR-knockout approach to identify new therapeutic targets contributing to the cancer supportive capacity of TME cells. Altogether, the overall aim of the proposed working plan is to provide a deeper understanding of the TME-related functions of protein kinases, fostering the redesigning of therapeutic applications in clinical trials, given the broad availability of kinase inhibitors.

通过小分子激酶抑制剂靶向B细胞受体（BCR）相关激酶已经产生了B淋巴恶性肿瘤如慢性淋巴细胞白血病（CLL）的治疗的巨大进展（Hallek等人，Lancet 2018）。在常规治疗中引入这些抑制剂后，出现了令人信服的证据，表明它们的疗效不仅依赖于对B细胞自主功能的抑制。相反，这些抑制剂的作用机制在很大程度上可以通过调节淋巴肿瘤微环境（TME）内的不同细胞类型来解释（Nguyen，Niesen，Hallek，Leukemia 2019）。最近，我们发现了林恩激酶（BCR的中心信号传导组分）在产生促恶性白血病微环境中的意外的有效功能作用（Nguyen et al.，Cancer Cell 2016）。特别地，我们观察到林恩激酶的存在是维持造血细胞和非造血细胞的白血病支持能力所必需的。此外，我们实验室的初步数据表明，Lyn-deficiency导致TME中巨噬细胞和成纤维细胞的深刻蛋白质组学变化。蛋白质组分析显示，在两种细胞类型中，Lyn诱导的变化几乎没有重叠，这表明林恩激活白血病相关巨噬细胞和成纤维细胞中不同的细胞类型特异性功能途径。该项目的中心假设是非受体酪氨酸激酶如林恩作为B细胞淋巴瘤的促肿瘤微环境的中心调节剂发挥作用。因此，对这些激酶在淋巴TME中的功能的更好的机制理解将有助于设计改进的抗淋巴瘤疗法。在第一个目标中，我们将验证新靶点的细胞类型特异性调节，包括不同TME细胞中林恩激酶调控网络内的转录因子。同时，我们将探讨林恩在成纤维细胞活化和诱导促癌表型中的潜在作用。在第二个目标中，我们将使用不同的体外和体内遗传工具来确定负责林恩的TME作用的结构信号传导结构域。在第三个目标中，我们将采用高含量、功能性阵列CRISPR敲除方法来鉴定有助于TME细胞癌症支持能力的新治疗靶点。总而言之，拟议工作计划的总体目标是提供对蛋白激酶TME相关功能的更深入了解，促进临床试验中治疗应用的重新设计，考虑到激酶抑制剂的广泛可用性。