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

描述(申请人提供)：癌症的特征是肿瘤细胞不受控制地生长，这些肿瘤细胞已知会影响间质中的邻近细胞，并特别招募巨噬细胞到原发肿瘤块中。随着对肿瘤相关巨噬细胞(TAMs)研究的不断深入，出现了一种适应性免疫系统“饲养”的图景，即肿瘤细胞将巨噬细胞招募到肿瘤微环境中，在那里它们影响巨噬细胞的信号通路，以实现生长和转移潜力。TAMs与预后不良和不断增加的转移性疾病有关，并逐渐被认为是恶性肿瘤的重要介质。经典激活的巨噬细胞通过Toll样受体(TLRs)传递信号，导致NF-κB的下游激活和促炎基因的转录。促进存活和在组织中坚持的信号可能有助于肿瘤的生长和转移。转化生长因子-β-激活激酶1是一种在多种细胞类型中参与促炎和细胞凋亡信号通路的激酶，包括促炎因子-κB和p38通路。TAK1有一个结合伙伴--TAK1相关结合蛋白1(TAB1)。我们最近的结果表明，TAK1的活性可能是巨噬细胞生存所必需的，但TAB1依赖的TAK1活性可能只是激活的巨噬细胞生存所必需的。由于已知TAMs高度激活，但具有持续的存活，我们假设TAK1是通过TAMS中的TAB1激活的，导致逃避细胞死亡。在缺乏TAB1的情况下，激活的巨噬细胞可能经历RIP1依赖的坏死。这种对TAB1的依赖可能代表了TAMs的一个脆弱性，因此TAB1的抑制可能成为抗癌治疗的潜在靶点。删除肿瘤细胞激活的巨噬细胞中的TAB1和TAK1，并测量和表征巨噬细胞的死亡将检验这一假说。将野生型或Tab1缺失的骨髓细胞移植到荷瘤小鼠体内，检测其对肿瘤大小、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。TAMs与肿瘤转移密切相关，并可能在某些肿瘤类型的转移中起重要作用。为了研究TAB1-TAK1信号在转移中的作用，将从高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。这将允许比较具有野生型或TAB1缺失的巨噬细胞的小鼠与没有成熟T细胞和B细胞的小鼠，从而有助于对存活所涉及的途径的具体了解。巨噬细胞和肿瘤细胞之间的细胞信号和通讯促进巨噬细胞存活，最终促进肿瘤的生长和转移。这项研究将填补我们对TAMS以及这些过程如何导致恶性肿瘤的理解的空白。破坏巨噬细胞-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和毒性更低的癌症治疗。

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-κB 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-κB 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.