Paracrine TGF-Beta Signaling in Tumor Initiation and Progression

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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 TGFbeta 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 TGFbeta 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.