? This proposal seeks to establish the Vanderbilt University Tumor Microenvironment Network (VUTMEN) to? contribute to the generation of a comprehensive understanding of the role of the tumor stroma in cancer? initiation, progression, and metastasis. The strategy used by the VUTMEN is to focus our efforts on? understanding the downstream mechanisms used by a critical biological mediator of host:tumor? interactions.TGFbeta. Project 1 uses sophisticated mouse genetics and advanced proteomic technologies to? identify the downstream effectors of tumor and stromal TGF|3 signaling pathways that influence mammary? gland tumorigenesis. Project 2 uses a combination of human prostate cancer and mouse model-derived? cells and the tissue recombination model to examine the effectors of TGFp that modulate prostatic? carcinogenesis. The role of TGFbeta in driving the vicious cycle that regulates the growth of breast metastases? in bone is the topic of Project 3. All results will be followed up in human tumor samples. The VUTMEN? supports 3 """"""""Integrative Shared Resources"""""""" that bring state-of-the-art technologies and a systems biology? approach to the three VUTMEN projects. The Protein Collection and Proteomics Core provides proteomic? technologies specifically relevant to the tumor microenvironment, including microdialysis and imaging mass? spectroscopy. The Image Fusion Core is devoted to novel imaging strategies that enhance the? understanding of the tumor microenvironment, including a multi-parametric and multi-modality approach? known as image fusion. The Biomathematics and Bioinformatics Core develops new approaches to? analyzing complex data sets and generates mathematical models for iterative hypothesis generation and? testing. We propose that the acknowledged complexity of the tumor microenvironment can be unraveled by? the strategy of focusing our efforts on the key regulatory pathway of TGFbeta. This will be achieved through the? systematic examination of known molecular modulators that are downstream of TGFbeta and the discovery of? new ones using proteomic approaches, examining biological effects in vivo in real time and correlating the? results with molecular parameters using genetic manipulation and image fusion technologies, using? mathematical modeling to iteratively generate hypotheses and test them experimentally, and comparing the? results in three distinct but related organ sites. Our goal is to generate a comprehensive understanding of? the mechanisms used by TGFbeta to control the reciprocal interactions between a tumor and its? microenvironment.? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA126505-02
Application #
7289826
Study Section
Special Emphasis Panel (ZCA1-SRRB-3 (O1))
Program Officer
Mohla, Suresh
Project Start
2006-09-25
Project End
2011-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$1,492,097
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Seeley, Erin H; Wilson, Kevin J; Yankeelov, Thomas E et al. (2014) Co-registration of multi-modality imaging allows for comprehensive analysis of tumor-induced bone disease. Bone 61:208-16
Johnson, Rachelle W; Merkel, Alyssa R; Page, Jonathan M et al. (2014) Wnt signaling induces gene expression of factors associated with bone destruction in lung and breast cancer. Clin Exp Metastasis 31:945-59
Pickup, Michael W; Laklai, Hanane; Acerbi, Irene et al. (2013) Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-?-deficient mouse mammary carcinomas. Cancer Res 73:5336-46
Jin, Renjie; Sterling, Julie A; Edwards, James R et al. (2013) Activation of NF-kappa B signaling promotes growth of prostate cancer cells in bone. PLoS One 8:e60983
Anderson, Philip D; McKissic, Sydika A; Logan, Monica et al. (2012) Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis. J Clin Invest 122:1907-19
Orr, B; Riddick, A C P; Stewart, G D et al. (2012) Identification of stromally expressed molecules in the prostate by tag-profiling of cancer-associated fibroblasts, normal fibroblasts and fetal prostate. Oncogene 31:1130-42
Thiolloy, Sophie; Edwards, James R; Fingleton, Barbara et al. (2012) An osteoblast-derived proteinase controls tumor cell survival via TGF-beta activation in the bone microenvironment. PLoS One 7:e29862
Basanta, D; Scott, J G; Fishman, M N et al. (2012) Investigating prostate cancer tumour-stroma interactions: clinical and biological insights from an evolutionary game. Br J Cancer 106:174-81
Li, Xiaohong; Sterling, Julie A; Fan, Kang-Hsien et al. (2012) Loss of TGF-? responsiveness in prostate stromal cells alters chemokine levels and facilitates the development of mixed osteoblastic/osteolytic bone lesions. Mol Cancer Res 10:494-503
Novitskiy, Sergey V; Pickup, Michael W; Chytil, Anna et al. (2012) Deletion of TGF-? signaling in myeloid cells enhances their anti-tumorigenic properties. J Leukoc Biol 92:641-51

Showing the most recent 10 out of 48 publications