TGF-li 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-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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA143057-02
Application #
8254379
Study Section
Special Emphasis Panel (ZCA1-SRLB-C (O1))
Program Officer
Mohla, Suresh
Project Start
2011-04-07
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$537,945
Indirect Cost
$141,941
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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) TGFβ-Mediated induction of SphK1 as a potential determinant in human MDA-MB-231 breast cancer cell bone metastasis. Bonekey Rep 4:719
Wright, Laura E; Buijs, Jeroen T; Kim, Hun-Soo et al. (2015) Single-Limb Irradiation Induces Local and Systemic Bone Loss in a Murine Model. J Bone Miner Res 30:1268-79
Fournier, Pierrick G J; Juárez, Patricia; Jiang, Guanglong et al. (2015) The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone. Cancer Cell 27:809-21
Waning, David L; Guise, Theresa A (2015) Cancer-associated muscle weakness: What's bone got to do with it? Bonekey Rep 4:691
Waning, David L; Mohammad, Khalid S; Reiken, Steven et al. (2015) Excess TGF-β mediates muscle weakness associated with bone metastases in mice. Nat Med 21:1262-71
Wright, Laura E; Guise, Theresa A (2014) The microenvironment matters: estrogen deficiency fuels cancer bone metastases. Clin Cancer Res 20:2817-9
Waning, David L; Guise, Theresa A (2014) Molecular mechanisms of bone metastasis and associated muscle weakness. Clin Cancer Res 20:3071-7
Guise, Theresa A (2013) Breast cancer bone metastases: it's all about the neighborhood. Cell 154:957-9
Wright, Laura E; Frye, Jennifer B; Lukefahr, Ashley L et al. (2013) Curcuminoids block TGF-β signaling in human breast cancer cells and limit osteolysis in a murine model of breast cancer bone metastasis. J Nat Prod 76:316-21

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