Paracrine TGF-Beta Signaling in Tumor Initiation and Progression

这项建议旨在建立范德比尔特大学肿瘤微环境网络(VUTMEN)，以促进对肿瘤间质在癌症发生、发展和转移中的作用的全面了解。VUTMEN使用的策略是将我们的努力集中在了解宿主的关键生物介质-肿瘤相互作用-TGFbeta所使用的下游机制上。项目1使用复杂的小鼠遗传学和先进的蛋白质组技术来确定影响乳腺肿瘤发生的肿瘤下游效应因子和基质转化生长因子β信号通路。项目2使用人类前列腺癌和小鼠模型衍生细胞的组合以及组织重组模型来检查调节前列腺癌发生的转化生长因子β的效应因子。TGFbeta在驱动恶性循环中的作用，调节乳腺转移瘤在骨中的生长是项目3的主题。所有结果都将在人类肿瘤样本中进行跟踪。VUTMEN支持三个“综合共享资源”，将最先进的技术和系统生物学方法引入VUTMEN的三个项目。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学。图像融合核心致力于新的成像策略，以增强对肿瘤微环境的理解，包括一种称为图像融合的多参数和多模式方法。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，通过将我们的努力集中在TGFbeta的关键调控途径上，可以解开公认的肿瘤微环境的复杂性。这将通过系统地检查TGFbeta下游的已知分子调节器和使用蛋白质组学方法发现新的分子调节器来实现，使用遗传操作和图像融合技术实时检查体内的生物效应并将结果与分子参数相关联，使用数学建模迭代地生成假说并进行实验验证，并在三个不同但相关的器官部位比较结果。我们的目标是对TGFbeta用于控制肿瘤与其微环境之间的相互作用的机制有一个全面的了解。

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.