In Project 4 of this PPG we seek to continue and expand the fundamental information gained from our highly interactive studies of HTLV-1, which causes an aggressive T-cell lymphoma initiated by the oncoprotein Tax. Our studies indicate that Tax-induced malignancies produce alterations in the tumor microenvironment that enhance tumor growth, bone destruction and severity of disease through the expression of bone-derived factors and cytokines that recruit host cells in the tumor microenvironment including osteoclasts and inflammatory cells. We developed animal models of Tax-induced malignancies and identified a variety of critical mediators of bone destruction and metastasis in the tumor microenvironment. During the past 4 years the Rosol and Weilbaecher labs developed their common interests in the pathogenesis of bone metastases and bone biology. These investigators join their expertise in the proposed Project 4 to better elucidate the molecular mechanisms of HTLV-1 Tax on skeletal metastases and humoral hypercalcemia of malignancy (HHM). In the proposed Project 4, we hypothesize that RANKL/RANK signaling is the critical common pathway by which Tax-induced factors alter the bone microenvironment to cause the bone destruction and paraneoplastic complications such as hypercalcemia. Based on our published studies and new data our highly interactive group seeks to identify mechanisms of Tax-induced alterations of the bone microenvironment that induce hypercalcemia and enhance tumor growth in bone. Therefore, we have focused our specific aims to: 1) Characterize the mechanism(s) by which Tax-induced tumor cells induce RANKL production and modulate of RANK signaling in osteolytic bone disease and humoral hypercalcemia of malignancy, 2) Define the molecular mechanisms by which tumor cells from Tax-induced malignancies alter normal osteoblast biology, 3) Define the molecular pathogenesis of a novel animal model of human osteosarcoma in Tax+Arf-/- mice. Thus, this evolution of Project 4 will address mechanisms of bone disease and metastasis and provide for rational design of interventions of life threatening complications of cancer in bone.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-S)
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Ohio State University
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Webb, Lindsay M; Amici, Stephanie A; Jablonski, Kyle A et al. (2017) PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis. J Immunol 198:1439-1451
Esser, Alison K; Rauch, Daniel A; Xiang, Jingyu et al. (2017) HTLV-1 viral oncogene HBZ induces osteolytic bone disease in transgenic mice. Oncotarget 8:69250-69263
Al-Saleem, Jacob; Kvaratskhelia, Mamuka; Green, Patrick L (2017) Methods for Identifying and Examining HTLV-1 HBZ Post-translational Modifications. Methods Mol Biol 1582:111-126
Fontana, Francesca; Ge, Xia; Su, Xinming et al. (2017) Evaluating Acetate Metabolism for Imaging and Targeting in Multiple Myeloma. Clin Cancer Res 23:416-429
Ratner, L; Rauch, D; Abel, H et al. (2016) Dose-adjusted EPOCH chemotherapy with bortezomib and raltegravir for human T-cell leukemia virus-associated adult T-cell leukemia lymphoma. Blood Cancer J 6:e408
Panfil, Amanda R; Martinez, Michael P; Ratner, Lee et al. (2016) Human T-cell leukemia virus-associated malignancy. Curr Opin Virol 20:40-46
Kawatsuki, A; Yasunaga, J-I; Mitobe, Y et al. (2016) HTLV-1 bZIP factor protein targets the Rb/E2F-1 pathway to promote proliferation and apoptosis of primary CD4(+) T cells. Oncogene 35:4509-17
Niewiesk, Stefan (2016) Animals Models of Human T Cell Leukemia Virus Type I Leukemogenesis. ILAR J 57:3-11
Su, Xinming; Esser, Alison K; Amend, Sarah R et al. (2016) Antagonizing Integrin ?3 Increases Immunosuppression in Cancer. Cancer Res 76:3484-95
Singh, Deepali; Boeras, Ioana; Singh, Gatikrushna et al. (2016) Isolation of Cognate Cellular and Viral Ribonucleoprotein Complexes of HIV-1 RNA Applicable to Proteomic Discovery and Molecular Investigations. Methods Mol Biol 1354:133-46

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