Tumor associated macrophages (TAM) constitute one of the major components of the immune cell infiltrate observed in the tumor microenvironment (TME) of virtually all types of malignancies. Emerging data implicates macrophages as key regulators of tumor cell proliferation, angiogenesis metastasis and survival. Many factors present within the TME including TGF-?, allow tumors to routinely circumvent host mediated immune responses and redirect TAM activities for successful tumor progression. However, the molecular mechanism(s) underlying such a process are not known. In early stages of carcinogenesis TGF-? acts as tumor suppressor and in late stages as tumor promoter. Consistent with the tumor promoting function, TGF-? is known to have a broader influence on the immune system partly through cross-talk between TGF-? signaling intermediates and the components of both cytokine and antigen receptors including Toll-like receptors. The family of Toll-Like Receptors (TLRs) is an important mediator of the innate immune responses by immune cells and activation of these receptors trigger the production of several molecules involved in antitumoral responses including IFNs. In TME, what exactly triggers TLR signaling in macrophages is not known. However, The TME is rich in host derived molecules, including heat shock proteins, double stranded DNA from necrotic tumor cells and Hyaluronic acid that can potentially activate macrophage TLR signaling to trigger anti-tumoral responses. IRAK-M is an inactive ser/thr kinase, potent negative regulator of TLR signaling and predominantly expressed in macrophages. Our studies show that when co-cultured, human lung cancer cells induce IRAK-M expression in human monocytes/macrophages. TGF-? induces IRAK-M expression in human monocytes/macrophages in time and dose dependent manner. In-vivo studies in IRAK-M-/- mice showed a significant inhibition in tumor growth of subcutaneously implanted syngeneic Lewis-lung carcinoma cells. Analysis of TAMs purified from wild type mice demonstrated enhanced IRAK-M expression compared to peritoneal macrophages from same mice. TAMs from IRAK-M-/- mice demonstrated enhanced expression of proinflammatory and anti-tumor cytokines. Hypothesis: Based on above observations, we propose that tumor cell production of TGF-? results in IRAK-M expression by TAMs which functions to antagonize TLR signaling. This allows tumors to circumvent potential TLR mediated anti-tumor responses of macrophages and contribute to acquisition of distinct TAM phenotype. Conversely, disruption of IRAK-M expression may promote anti-tumor responses in TAMs and inhibit tumor growth and metastasis.
Specific aims : 1) to determine the role of IRAK-M in lung tumor growth and metastasis using syngeneic heterotopic and orthotopic models of lewis lung carcinoma in IRAK-M-/- mice. 2) to determine the contribution of IRAK-M to the immunosuppressive phenotype of TAMs. 3) to determine whether the primary effector cell critical for tumor growth inhibition in IRAK-M-/- mice is of myeloid origin, by bone marrow transplantation 4) determine the mechanism of TGF-?-induced IRAK-M expression in macrophages.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132571-05
Application #
8247104
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (O1))
Program Officer
Mccarthy, Susan A
Project Start
2008-05-05
Project End
2013-10-30
Budget Start
2012-05-01
Budget End
2013-10-30
Support Year
5
Fiscal Year
2012
Total Cost
$278,574
Indirect Cost
$94,274
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Reka, Ajaya Kumar; Chen, Guoan; Jones, Richard C et al. (2014) Epithelial-mesenchymal transition-associated secretory phenotype predicts survival in lung cancer patients. Carcinogenesis 35:1292-300
Standiford, T J; Kuick, R; Bhan, U et al. (2011) TGF-?-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth. Oncogene 30:2475-84
Reka, Ajaya Kumar; Goswami, Moloy T; Krishnapuram, Rashmi et al. (2011) Molecular cross-regulation between PPAR-? and other signaling pathways: implications for lung cancer therapy. Lung Cancer 72:154-9
Reka, Ajaya Kumar; Kuick, Rork; Kurapati, Himabindu et al. (2011) Identifying inhibitors of epithelial-mesenchymal transition by connectivity map-based systems approach. J Thorac Oncol 6:1784-92
Cavassani, Karen A; Carson 4th, William F; Moreira, Ana Paula et al. (2010) The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth. Blood 115:4403-11
Sartor, Maureen A; Mahavisno, Vasudeva; Keshamouni, Venkateshwar G et al. (2010) ConceptGen: a gene set enrichment and gene set relation mapping tool. Bioinformatics 26:456-63
Maupin, Kevin A; Sinha, Arkadeep; Eugster, Emily et al. (2010) Glycogene expression alterations associated with pancreatic cancer epithelial-mesenchymal transition in complementary model systems. PLoS One 5:e13002
Reka, Ajaya Kumar; Kurapati, Himabindu; Narala, Venkata R et al. (2010) Peroxisome proliferator-activated receptor-gamma activation inhibits tumor metastasis by antagonizing Smad3-mediated epithelial-mesenchymal transition. Mol Cancer Ther 9:3221-32
Keshamouni, Venkateshwar G; Schiemann, William P (2009) Epithelial-mesenchymal transition in tumor metastasis: a method to the madness. Future Oncol 5:1109-11
Keshamouni, Venkateshwar G; Jagtap, Pratik; Michailidis, George et al. (2009) Temporal quantitative proteomics by iTRAQ 2D-LC-MS/MS and corresponding mRNA expression analysis identify post-transcriptional modulation of actin-cytoskeleton regulators during TGF-beta-Induced epithelial-mesenchymal transition. J Proteome Res 8:35-47