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：
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
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/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

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-?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.