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

TAB1-TAK1 信号传导在肿瘤相关巨噬细胞存活中的作用

• 批准号: 8526774
• 负责人: September R Mihaly
• 金额: $ 3.18万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-31 至 2015-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526774
• 关键词: Ablation; Affect; Alleles; Antioxidants; Apoptotic; B-Lymphocytes; Binding; Binding Proteins; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Breeding; Cancer cell line; Cell Communication; Cell Death; Cell Line; Cell Survival; Cells; Chemotherapy-Oncologic Procedure; Coculture Techniques; Dependency; Development; Disease; Drug Targeting; Gene Expression Profile; Genes; Genetic Transcription; Growth; Hematopoietic; Human; Immune system; Inflammatory; Interleukin-1; K-ras Gene; Knock-out; Knowledge; Lead; Lewis Lung Carcinoma; Lung Neoplasms; MAP kinase kinase kinase 7; MAP3K7 gene; MAPK14 gene; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mammary Neoplasms; Mature T-Lymphocyte; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Necrosis; Neoplasm Metastasis; Oncogenic; Outcome; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Primary Neoplasm; Process; Publishing; Rag1 Mouse; Reactive Oxygen Species; Recruitment Activity; Research; Role; Series; Signal Pathway; Signal Transduction; Stimulus; T-Lymphocyte; TNF gene; Tamoxifen; Testing; Tissue Model; Tissues; Toll-like receptors; Transgenic Mice; Transplantation; Xenograft procedure; cancer therapy; cell type; chemotherapy; cytokine; established cell line; human MAP3K7 protein; inhibitor/antagonist; killings; macrophage; neoplastic cell; novel; outcome forecast; prevent; protein protein interaction; public health relevance; research study; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

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.

描述（由申请人提供）：癌症的特征在于肿瘤细胞的不受控制的生长，并且已知这些肿瘤细胞影响基质中的邻近细胞，并特异性地将巨噬细胞募集到原发性肿瘤块。随着肿瘤相关巨噬细胞（TAM）研究的发展，适应性免疫系统“饲养”的画面正在出现，其中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中的细胞信号传导途径以实现生长和转移潜力。TAM与不良预后和日益增加的转移性疾病相关，并且逐渐被认为是恶性肿瘤的重要介质。经典激活的巨噬细胞涉及信号通过Toll样受体（TLR），导致下游激活NF-？B和促炎基因的转录。促进TAM存活和在组织中持续存在的信号可能有助于肿瘤生长和转移。TGF-β激活激酶1（TAK 1）是一种已知在几种细胞类型中参与促炎和凋亡细胞信号通路的激酶，包括促炎NF-？B和p38通路。TAK 1有一个结合伴侣，TAK 1相关结合蛋白1（TAB 1）。我们最近的研究结果表明，TAK 1的活性可能是必不可少的巨噬细胞的生存，但TAB 1依赖的TAK 1活性可能只需要激活巨噬细胞的生存。因为已知TAM是高度活化的，但具有持续的存活，我们假设TAK 1在TAM中通过TAB 1被活化，导致细胞逃避死亡。在缺乏TAB 1的情况下，活化的巨噬细胞可能发生RIP 1依赖性坏死。这种TAB 1依赖性可能代表TAM的脆弱性，因此TAB 1的抑制可能是抗癌治疗的潜在靶点。删除肿瘤细胞激活的巨噬细胞中的TAB 1和TAK 1并测量和表征巨噬细胞死亡将检验这一假设。将野生型或Tab 1缺失的骨髓细胞移植到荷瘤小鼠中并测量对肿瘤大小和多样性以及对巨噬细胞存活的影响将有助于确定TAB 1和TAK 1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所必需的。为了研究TAB 1-TAK 1信号传导在转移中的作用，将从高转移性人乳腺肿瘤建立的细胞系注射到Rag 1缺陷和Tab 1-Rag 1双缺陷小鼠中。这将允许在不存在成熟T细胞和B细胞的情况下比较具有野生型或Tab 1缺失的巨噬细胞的小鼠，从而有助于对TAM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传导和通信促进巨噬细胞存活并最终促进肿瘤生长和转移。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-肿瘤细胞相互作用以及巨噬细胞内的信号传导途径可能导致更有效和毒性更小的癌症治疗。