Paracrine TGF-Beta Signaling in Tumor Initiation and Progression

该提案旨在建立范德比尔特大学肿瘤微环境网络（VUTMEN），以促进全面了解肿瘤基质在癌症发生、进展和转移中的作用。VUTMEN使用的策略是将我们的努力集中在理解宿主的关键生物介质所使用的下游机制：肿瘤相互作用。项目1使用复杂的小鼠遗传学和先进的蛋白质组学技术来鉴定影响乳腺肿瘤发生的肿瘤和基质TGF β信号通路的下游效应物。项目2使用人前列腺癌和小鼠模型衍生细胞和组织重组模型的组合来检查调节前列腺癌发生的TGF β效应物。TGF β在驱动调节乳腺癌骨转移生长的恶性循环中的作用是项目3的主题。所有结果将在人肿瘤样本中进行随访。VUTMEN支持3个“综合共享资源”，为三个VUTMEN项目带来最先进的技术和系统生物学方法。蛋白质收集和蛋白质组学核心提供与肿瘤微环境特别相关的蛋白质组学技术，包括微透析和成像质谱。Image Fusion Core致力于增强对肿瘤微环境的理解的新型成像策略，包括称为图像融合的多参数和多模态方法。生物数学和生物信息学核心开发了分析复杂数据集的新方法，并为迭代假设生成和测试生成数学模型。我们认为，肿瘤微环境的公认复杂性可以通过将我们的努力集中在TGF β的关键调控途径上的策略来解开。这将通过系统地检查已知的TGF β下游的分子调节剂和使用蛋白质组学方法发现新的分子调节剂来实现，在真实的时间内检查体内生物效应并使用遗传操作和图像融合技术将结果与分子参数相关联，使用数学建模来迭代地产生假设并通过实验对其进行测试，并比较三个不同但相关的器官部位的结果我们的目标是全面了解TGF β用于控制肿瘤及其微环境之间相互作用的机制。

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.