Role of TAB1-TAK1 signaling in tumor-associated macrophage survival

描述（由申请人提供）：癌症的特点是肿瘤细胞生长不受控制，已知这些肿瘤细胞会影响基质中的邻近细胞，并特异性地将巨噬细胞招募到原发肿瘤肿块。随着对肿瘤相关巨噬细胞（tumor associated macrophages, tam）研究的不断深入，一种适应性免疫系统的“饲养”机制正在形成，肿瘤细胞将巨噬细胞招募到肿瘤微环境中，影响巨噬细胞的细胞信号通路，从而实现巨噬细胞的生长和转移潜能。tam与不良预后和越来越多的转移性疾病相关，并逐渐被认为是恶性肿瘤的重要介质。经典活化的巨噬细胞通过toll样受体（TLRs）发出信号，导致下游NF-？B和促炎基因的转录。促进组织中TAM存活和持续的信号可能有助于肿瘤的生长和转移。tgf - β活化激酶1 （TAK1）是一种在几种细胞类型中已知的参与促炎和凋亡细胞信号通路的激酶，包括促炎的NF-？B和p38通路。TAK1有一个结合伙伴，TAK1相关结合蛋白1 （TAB1）。我们最近的研究结果表明，TAK1的活性可能对巨噬细胞的存活至关重要，但tab1依赖性的TAK1活性可能仅对活化的巨噬细胞存活是必需的。由于已知tam具有高度激活但持续存活的特性，我们假设TAK1通过tam中的TAB1被激活，从而导致细胞免于死亡。在缺乏TAB1的情况下，活化的巨噬细胞可能发生rip1依赖性坏死。这种对TAB1的依赖性可能代表了tam的脆弱性，因此抑制TAB1可能是抗癌治疗的潜在靶点。在肿瘤细胞活化的巨噬细胞中删除TAB1和TAK1并测量和表征巨噬细胞的死亡将验证这一假设。将野生型或缺失TAB1的骨髓细胞移植到荷瘤小鼠体内，测量其对肿瘤大小、多样性和巨噬细胞存活的影响，将有助于确定TAB1和TAK1在肿瘤发生中的作用。tam与转移有关，并且可能是某些肿瘤类型转移的必要条件。为了研究Tab1- tak1信号在转移中的作用，我们将从高度转移的人乳腺肿瘤中建立的细胞系注射到rag1缺陷和Tab1- rag1双缺陷小鼠中。这将允许在缺乏成熟T细胞和B细胞的情况下比较野生型或tab1缺失巨噬细胞的小鼠，从而提供与TAM存活相关的途径的特定知识。巨噬细胞与肿瘤细胞之间的细胞信号传导和通讯促进了巨噬细胞的存活，最终促进了肿瘤的生长和转移。这项研究将填补我们对tam的理解以及这些过程如何导致恶性肿瘤的空白。破坏巨噬细胞与肿瘤细胞的相互作用以及巨噬细胞内的信号通路可能会导致更有效、毒性更小的癌症治疗。

DESCRIPTION (provided by applicant): Cancer is characterized by the uncontrolled growth of tumor cells, and these tumor cells are known to affect neighboring cells in the stroma and specifically recruit macrophages to the primary tumor mass. As research in tumor-associated macrophages (TAMs) evolves, a picture of adaptive immune system "husbandry" is emerging, in which tumor cells recruit macrophages to the tumor microenvironment where they affect cell signaling pathways in macrophages to achieve growth and metastatic potential. TAMs are associated with poor prognosis and increasingly metastatic disease, and are coming to be recognized as important mediators of malignancy. The classically activated macrophage involves signaling through Toll-like receptors (TLRs), leading to downstream activation of NF-?B and the transcription of pro-inflammatory genes. Signals that promote TAM survival and persistence in tissues could contribute to tumor growth and metastasis. TGF-beta-activated kinase 1 (TAK1) is a kinase that is known in several cell types to be involved in pro-inflammatory and apoptotic cell signaling pathways, including the pro-inflammatory NF-?B and p38 pathways. TAK1 has a binding partner, TAK1-associated binding protein 1 (TAB1). Our recent results suggest that activity of TAK1 may be essential for macrophage survival, but TAB1-dependent TAK1 activity may be required only for activated macrophage survival. Because TAMs are known to be highly activated but with sustained survival, we hypothesize that TAK1 is activated through TAB1 in TAMs, resulting in escape from cell death. In the absence of TAB1, activated macrophages may undergo RIP1-dependent necrosis. This TAB1 dependency may represent a vulnerability in TAMs, and the inhibition of TAB1 may therefore be a potential target for anti-cancer therapy. Deleting TAB1 and TAK1 in tumor cell-activated macrophages and measuring and characterizing macrophage cell death will test this hypothesis. Transplanting wild type or Tab1-deleted bone marrow cells into tumor- bearing mice and measuring the effects on tumor size and multiplicity and on macrophage survival will help to determine the roles of TAB1 and TAK1 in tumorigenesis. TAMs have been implicated in metastasis, and may be essential for metastasis of some tumor types. To investigate the role of TAB1-TAK1 signaling in metastasis, cell lines established from highly metastatic human mammary tumors will be injected in Rag1-deficient and Tab1- Rag1-double-deficient mice. This will allow for comparing mice having wild type or Tab1-deleted macrophages in the absence of mature T cells and B cells, thereby contributing specific knowledge of the pathways involved in TAM survival. Cell signaling and communication between macrophages and tumor cells promote macrophage survival and ultimately tumor growth and metastasis. This study will fill in gaps in our understanding of TAMs and how these processes contribute to malignancy. Disrupting macrophage-tumor cell interactions as well as signaling pathways within macrophages could lead to more effective and less toxic cancer therapies.