TGF-li plays a central role in bone is released in high concerntrations from bone during osteo- clastic bone resorption, a process that is active in all bone metastases.TGF-S enhances tumor factors that increase osteolytic bone destruction.The actions of TGF-B on osteoblasts &osteoclasts &consequent contributions to tumor growth in bone are less well characterized. We hypothesize that, in addition to its effects on tumor cells, TGF-li acts on osteoblasts to regulate factors, such as Wnt ligands and BMP antagonists, which have differing effects on the growth of osteolytic vs osteoblastic tumor types. In addition,TGF-B activates osteoclasts to increase bone resorption in all types of skeletal mestastases. Dr. Neil Bhowmick, Vanderbilt University Tumor Microenvironment Network (VUTMEN), &Dr. Theresa Guise, Indiana University, will study the role of TGF-B signaling in osteoblasts &osteoclasts in the bone microenvironment and the effect on bone metastases. The Pi's will test:Hypothesis 1 TGF-B signaling in osteoblasts regulates tumor growth in bone, &the responses are dependent on whether the tumor is predominantly osteolytic or osteoblastic.
Aim 1. Determine the role of osteoblastic responsiveness to TGF-B in the establishment and progression of bone metastases of all types: Mice with osteoblasts-targeted deletion or activation of TGF-B signaling will be generated &the effect on bone metastases by osteolytic, osteoblastic or mixed tumors of breast, prostate, &melanoma will be studied. Hypothesis 2:TGF-B signaling in osteoclasts increases bone resorption, favoring tumor growth in bone, independent ofthe type of bone metastasis.
Aim 2. Determine the role of osteoclastic responsiveness to TGF-B in the establishment and progression of all types of bone metastases.Mice with osteoclast targeted deletion or activation of TGF-B signaling will be generated &the effect on bone metastases will be studied as in Aim 1. Hypothesis 3: Osteoblasts respond to TGF-B via secretion of factors, in a StatS-dependent manner, to alter tumor behavior in bone.
Aim 3. Identify mechanisms of TGF-(3-mediated paracrine regulation of metastatic tumor growth in bone: the role of Stat3 regulation of wntSa and chordin will be studied in mouse models and human tissue.

Public Health Relevance

The goal of our research is to improve treatment and prevent bone metastases. We will compare bone cell specific alterations in TGF-B signaling (host) with systemic inhibition of TGF-B (host &tumor). The novel models of bone cell-specific alterations in TGF-B signaling will give unique insight to target TGF-B to treatbone metastases and will complement sudles on TGF-B on the tumor microenvironment at VUTMEN.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZCA1)
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Mohla, Suresh
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Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
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Juárez, Patricia; Fournier, Pierrick G J; Mohammad, Khalid S et al. (2017) Halofuginone inhibits TGF-?/BMP signaling and in combination with zoledronic acid enhances inhibition of breast cancer bone metastasis. Oncotarget 8:86447-86462
Regan, Jenna N; Trivedi, Trupti; Guise, Theresa A et al. (2017) The Role of TGF? in Bone-Muscle Crosstalk. Curr Osteoporos Rep 15:18-23
Trivedi, Trupti; Zheng, Yu; Fournier, Pierrick G J et al. (2017) The vitamin D receptor is involved in the regulation of human breast cancer cell growth via a ligand-independent function in cytoplasm. Oncotarget 8:26687-26701
Wright, Laura E; Harhash, Ahmed A; Kozlow, Wende M et al. (2017) Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo. Oncotarget 8:8406-8419
Regan, Jenna N; Mikesell, Carter; Reiken, Steven et al. (2017) Osteolytic Breast Cancer Causes Skeletal Muscle Weakness in an Immunocompetent Syngeneic Mouse Model. Front Endocrinol (Lausanne) 8:358
Tripathi, Manisha; Nandana, Srinivas; Billet, Sandrine et al. (2017) Modulation of cabozantinib efficacy by the prostate tumor microenvironment. Oncotarget 8:87891-87902
Mohammad, Khalid S; Guise, Theresa A (2016) Hypercalcemia of Malignancy: A New Twist on an Old Problem. J Oncol Pract 12:435-6
Zhang, Peng; Xing, Caihong; Rhodes, Steven D et al. (2016) Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice. Stem Cell Reports 6:914-25
Regan, Jenna N; Waning, David L; Guise, Theresa A (2016) Skeletal muscle Ca(2+) mishandling: Another effect of bone-to-muscle signaling. Semin Cell Dev Biol 49:24-9
Stayrook, Keith R; Mack, Justin K; Cerabona, Donna et al. (2015) TGF?-Mediated induction of SphK1 as a potential determinant in human MDA-MB-231 breast cancer cell bone metastasis. Bonekey Rep 4:719

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