The general goal of the proposed research is to understand how cancer associated stroma, including cancer associated fibroblast (CAF), tumor infiltrating lymphocytes (TIL) and their interactions with carcinoma cells contributes to pulmonary metastasis of breast cancer. CAF and TIL are critically involved in mammary tumorigenesis and metastasis. To address the role of CAF and TIL in pulmonary metastasis of mammary cancer, we have established several spontaneous and transplant mammary tumor models. Our research demonstrates that receptor for activated nuclear factor ?B ligand (RANKL) is expressed by tumor infiltrating CD4+ T cells, mainly Treg cells in tumor associated stroma. RANKL activates its cognate receptor RANK on cell surface of carcinoma cells, which leads to the activation and nuclear translocation of IKK? and in turn the repression of maspin, a key metastasis inhibitor in a variety of cancers. However, the links between carcinoma cells, CAF, and CD4+CD25+ T cells still remain obscure. I therefore propose to pursue the following aims: Identify other factors from CAFs responsible for Treg cell infiltration into tumor;Identify signaling pathway that controls chemokine expression from CAF; Examine the role of carcinoma cells in fibroblast activation;Examine the role of alternative NF-?B pathways components, including NF-?B inducing kinase (NIK), TRAF2, and TRAF3 in ErbB2-induced mammary tumor development and metastasis;and identify upstream members, if other than RANKL that activates NIK/IKK? during mammary tumorigenesis. The proposed studies are innovative as they address a poorly explored and controversial research problem with great clinical significance and public health importance.

Public Health Relevance

Breast cancer is second common malignancy and the leading cause of cancer-related mortality amongst women in the US, mainly caused by metastatic spread of advanced tumors to bone, lung, brain and liver. This proposal will focus on the interplays between tumor associated stoma, mainly CAFs, and tumor-infiltrating T cells and carcinoma cells. This proposed study should shed light on the understanding of fundamental role of inflammatory signals in pulmonary metastasis and reveal potential targets of great importance leading to the cure for mammary cancer metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Transition Award (R00)
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Mohla, Suresh
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University of Iowa
Schools of Medicine
Iowa City
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Ren, Ruotong; Deng, Liping; Xue, Yanhong et al. (2017) Visualization of aging-associated chromatin alterations with an engineered TALE system. Cell Res 27:483-504
Yang, Jiping; Li, Jingyi; Suzuki, Keiichiro et al. (2017) Genetic enhancement in cultured human adult stem cells conferred by a single nucleotide recoding. Cell Res 27:1178-1181
Liu, Q; Kulak, M V; Borcherding, N et al. (2017) A novel HER2 gene body enhancer contributes to HER2 expression. Oncogene :
Pan, Huize; Guan, Di; Liu, Xiaomeng et al. (2016) SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res 26:190-205
Yuan, Fang; Kolb, Ryan; Pandey, Gaurav et al. (2016) Involvement of the NLRC4-Inflammasome in Diabetic Nephropathy. PLoS One 11:e0164135
Li, Ying; Zhang, Weizhou; Chang, Liang et al. (2016) Vitamin C alleviates aging defects in a stem cell model for Werner syndrome. Protein Cell 7:478-88
Janowski, Ann M; Colegio, Oscar R; Hornick, Emma E et al. (2016) NLRC4 suppresses melanoma tumor progression independently of inflammasome activation. J Clin Invest 126:3917-3928
Kolb, Ryan; Sutterwala, Fayyaz S; Zhang, Weizhou (2016) Obesity and cancer: inflammation bridges the two. Curr Opin Pharmacol 29:77-89
Kusner, David; Borcherding, Nicholas; Zhang, Weizhou (2016) Paracrine WNT5A signaling in healthy and neoplastic mammary tissue. Mol Cell Oncol 3:e1040145
Kolb, Ryan; Phan, Liem; Borcherding, Nicholas et al. (2016) Obesity-associated NLRC4 inflammasome activation drives breast cancer progression. Nat Commun 7:13007

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