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.

Public Health Relevance

The innate immune system cell type known as macrophages have been found to contribute to cancer development and metastasis, and high numbers of macrophages are associated with worse outcomes for patients. The proposed experiments will increase our understanding of the pathways within macrophages that help these cells to survive in the tumor microenvironment. Results of our study may lead to the development of drugs that target these tumor-associated macrophages, which could be less harmful to the patient than current chemotherapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Schmidt, Michael K
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North Carolina State University Raleigh
Public Health & Prev Medicine
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United States
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Mihaly, September R; Sakamachi, Yosuke; Ninomiya-Tsuji, Jun et al. (2017) Noncanocial cell death program independent of caspase activation cascade and necroptotic modules is elicited by loss of TGF?-activated kinase 1. Sci Rep 7:2918
Mihaly, S R; Ninomiya-Tsuji, J; Morioka, S (2014) TAK1 control of cell death. Cell Death Differ 21:1667-76
Mihaly, September R; Morioka, Sho; Ninomiya-Tsuji, Jun et al. (2014) Activated macrophage survival is coordinated by TAK1 binding proteins. PLoS One 9:e94982