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

基本信息

批准号：
8722843
负责人：
September R Mihaly
金额：
$ 3.23万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
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/8722843
关键词：
Ablation Affect 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 Health Hematopoietic Human Immune system Inflammatory Interleukin-1 K-ras Gene Knock-out Knowledge Lead Lewis Lung Carcinoma LoxP-flanked allele 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 Tamoxifen Testing Tissue Model Tissues Toll-like receptors Transgenic Mice Transplantation Tumor Necrosis Factor-alpha 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 research study tumor tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

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.

描述（由适用提供）：癌症的特征是肿瘤细胞的不受控制，这些肿瘤细胞被已知会影响基质中的邻近细胞，并特别募集了巨噬细胞到原发性肿瘤质量。随着肿瘤相关巨噬细胞（TAMS）的研究的发展，适应性免疫系统“饲养”的图像正在出现，其中肿瘤细胞将巨噬细胞募集到肿瘤微环境中，它们会影响巨噬细胞中细胞信号途径，以实现生长和转移性潜力。 TAM与预后不良和越来越多的转移性疾病有关，并且被认为是重要的恶性介体。经典活化的巨噬细胞涉及通过Toll样受体（TLR）信号传导，导致NF-κB的下游激活和促炎基因的转录。促进组织中TAM生存和持久性的信号可能导致肿瘤生长和转移。 TGF-β激活的激酶1（TAK1）是一种激酶，在几种细胞类型中已知，涉及促炎和凋亡细胞信号通路，包括促炎性NF-κB和p38途径。 TAK1具有结合伴侣，与TAK1相关的结合蛋白1（TAB1）。我们最近的结果表明，tak1的活性对于巨噬细胞存活可能至关重要，但是只有激活的巨噬细胞存活可能需要TAB1依赖性TAK1活性。由于已知TAM被高度激活，但具有持续的存活，因此我们假设TAK1通过TAM1在TAM中激活，从而导致逃避细胞死亡。在没有TAB1的情况下，活化的巨噬细胞可能会发生RIP1依赖性坏死。此TAB1依赖性可能代表TAM中的脆弱性，因此TAB1的抑制可能是抗癌治疗的潜在靶标。在肿瘤细胞激活的巨噬细胞中删除TAB1和TAK1，并测量和表征巨噬细胞死亡将检验该假设。将野生型或TAB1骨髓细胞移植到肿瘤轴承小鼠中，并测量对肿瘤大小，多样性以及对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已在转移中隐含，对于某些肿瘤类型的转移可能至关重要。为了研究TAB1-TAK1信号在转移中的作用，将在RAG1缺乏和TAB1-RAG1双缺陷小鼠中注入由高度转移性人类乳腺肿瘤建立的细胞系。这将允许在没有成熟的T细胞和B细胞的情况下比较具有野生型或TAB1污染巨噬细胞的小鼠，从而对TAM存活中涉及的途径的特定知识进行了特定的了解。巨噬细胞和肿瘤细胞之间的细胞信号传导和通信可促进巨噬细胞的存活以及最终的肿瘤生长和转移。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。破坏巨噬细胞肿瘤的细胞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较小的癌症疗法。