Dissecting Lymphoma Niche Interactions

剖析淋巴瘤利基相互作用

• 批准号: 349194503
• 负责人: Professor Dr. Marc Schmidt-Supprian
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin III: Hämatologie und Onkologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/349194503?language=en
• 关键词: Dissecting; Lymphoma; Niche; Interactions

Lymphomas, the most prevalent cancer of immune cells require contact to various other cell-types in their direct vicinity, collectively referred to as niche. When taken out of an organism and cultured in absence of supporting niche cells, lymphoma cells typically die quickly. Therefore, niche cells are essential for the survival and proliferation of lymphoma cells in vivo and in vitro, through secreted soluble factors and cell-cell contacts. In recent years, it became clear that lymphomas do not simply settle in preformed niches, but in contrast actively induce a niche microenviroment that then sends critical survival signals back to the lymphoma cells. Chronic lymphocytic leukemia (CLL) is an essentially incurable disease of cancerous B cells that expand and survive in niches at different bodily locations. Niche cells also provide protection for CLL cells against cytotoxic therapies and therefore contribute essentially to therapy resistance. CLL cells induce activation of the NF-kappaB family of transcription factors in stromal cells, which control the production of essential proteins for the survival of CLL cells. This occurs through the induction of the PKCbeta-II kinase in stromal cells, an important niche subpopulation, through signals initiated via direct CLL-stroma interactions. The relevance of this signaling pathway was unambiguously demonstrated through adoptive transfer of mouse Tcl1tg CLL cells into wild-type mice and mice lacking PKCbeta: malignant CLL cells only expanded in wild-type, but not in PKCbeta-deficient mice. In our proposal we will test various relevant proteins and cellular pathways, which are induced by CLL cells in the stroma for their role in providing survival signals back to the CLL cells. The effects will be monitored in absence and presence of cytotoxic chemotherapies. Furthermore, we will investigate the CLL-induced signals in stromal niche cells in detail and test the hypothesis that CLL cells carrying mutations that provide therapy-resistance induce different signals. Finally, we will employ a preclinical mouse model to characterize the CLL-maintaining niche subpopulations in vivo and to dissect their individual and potentially redundant roles in CLL support.

淋巴瘤是最常见的免疫细胞癌症，需要与其直接附近的各种其他细胞类型接触，统称为生态位。当从生物体中取出并在缺乏支持性微环境细胞的情况下培养时，淋巴瘤细胞通常会很快死亡。因此，微环境细胞通过分泌的可溶性因子和细胞与细胞的接触，对于淋巴瘤细胞在体内和体外的存活和增殖至关重要。近年来，人们清楚地认识到，淋巴瘤并不是简单地定居在预先形成的生态位中，而是主动诱导生态位微环境，然后将关键的生存信号发送回淋巴瘤细胞。慢性淋巴细胞白血病 (CLL) 是一种本质上无法治愈的癌症 B 细胞疾病，这些细胞在身体不同部位的微环境中增殖和存活。生态位细胞还为 CLL 细胞提供针对细胞毒性治疗的保护，因此在很大程度上导致了治疗耐药性。 CLL 细胞诱导基质细胞中转录因子 NF-kappaB 家族的激活，该家族控制 CLL 细胞生存所需蛋白质的产生。这是通过直接 CLL-基质相互作用引发的信号，在基质细胞（一个重要的利基亚群）中诱导 PKCbeta-II 激酶而发生的。通过将小鼠 Tcl1tg CLL 细胞过继转移到野生型小鼠和缺乏 PKCbeta 的小鼠中，明确证明了该信号通路的相关性：恶性 CLL 细胞仅在野生型小鼠中扩增，但在 PKCbeta 缺陷小鼠中不扩增。在我们的提案中，我们将测试各种相关的蛋白质和细胞途径，这些蛋白质和细胞途径是由基质中的 CLL 细胞诱导的，因为它们在向 CLL 细胞提供生存信号方面发挥着作用。将在不存在和存在细胞毒性化疗的情况下监测效果。此外，我们将详细研究基质微环境细胞中 CLL 诱导的信号，并检验携带提供治疗抗性的突变的 CLL 细胞诱导不同信号的假设。最后，我们将采用临床前小鼠模型来表征体内维持 CLL 的利基亚群，并剖析它们在 CLL 支持中的个体和潜在冗余作用。