TGF-ß plays a central role in bone metastases.lt is released in high concerntrations from bone during osteo- clastic bone resorption, a process that is active in all bone metastases.TGF-ß enhances tumor factors that increase osteolytic bone destruction.The actions of TGF-ß 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-ß 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-ß 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-ß signaling in osteoblasts & osteoclasts in the bone microenvironment and the effect on bone metastases. The Pi's will test:Hypothesis 1 TGF-ß 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-ß in the establishment and progression of bone metastases of all types: Mice with osteoblasts-targeted deletion or activation of TGF-ß 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-ß 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-ß in the establishment and progression of all types of bone metastases.Mice with osteoclast targeted deletion or activation of TGF-ß signaling will be generated & the effect on bone metastases will be studied as in Aim 1. Hypothesis 3: Osteoblasts respond to TGF-ß via secretion of factors, in a StatS-dependent manner, to alter tumor behavior in bone. Aim 3. Identify mechanisms of TGF-ß-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.

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