Engineered ECM platforms to analyze progression in high grade serous ovarian cancer

项目摘要 虽然标准生物学方法如二维、体外细胞培养和体内动物模型被广泛使用， 癌症的复杂性需要一个连续的模型系统，这对研究某些生物学问题是有用的。 在这项工作中，我们建议通过采用多种创新技术为肿瘤组织工程奠定基础。 首先表征然后构建细胞外基质（ECM）仿生模型的方法 肿瘤微环境ECM是仿生学中的一个关键因素，在生物学中特别重要。 在癌症的背景下，ECM的组成和结构随着疾病而急剧变化 进展 我们将特别关注高级别浆液性卵巢癌（HGSOC），它与以下因素相关： 存活率特别差，不到50%。HGSOC起源于输卵管，转移到输卵管， 卵巢，然后通过腹膜扩散到器官，如网膜和小肠 肠系膜人们认识到需要更多的模型来研究HGSOC，而现有的模型还没有 检查ECM组成或结构变化的影响。使用最先进的质谱仪， 影像技术和彻底的免疫组织化学分析，我们将描述之间的差异， 在疾病的不同阶段，正常和患病组织的ECM。我们将利用创新的工程 包括组织工程和微制造的方法，以重建组织特异性病理生理学， HGSOC的背景下，并检查ECM组成和结构的变化对细胞的影响， 行为。通过这些实验结合计算/统计分析，我们将确定 我们发现的许多变化中的哪一个是导致疾病进展的原因。我们开发的模型将 对HGSOC的研究产生了变革性的影响，从我们的过程中吸取的经验教训可以应用于 广泛地朝向开发所有癌症类型的病理生理学相关模型的更大目标。

PROJECT SUMMARY While standard biological methods such as two-dimensional, in vitro cell culture and in vivo animal models are useful to examine certain biological questions, the complexity of cancer requires a continuum of model systems. In this work, we propose to create a foundation for tumor tissue engineering by employing multiple innovative methodologies to first characterize and then build biomimetic models of the extracellular matrix (ECM) in the tumor microenvironment. The ECM is a key element in biomimicry, and particularly important to consider in the context of cancer, where the composition and architecture of the ECM change drastically with disease progression. We will specifically focus upon high-grade serous ovarian cancer (HGSOC), which is associated with a particularly poor survival rate of less than 50%. HGSOC originates in the fallopian tube, metastasizes to the ovary, and then disseminates throughout the peritoneum to organs such as the omentum and small bowel mesentery. There is a recognized for additional models to study HGSOC, and the existing models have not examined the impact of variations in ECM composition or structure. Using state-of-the-art mass spectrometry, imaging technologies and thorough immunohistochemical analysis, we will characterize differences between the ECM of normal and diseased tissues across the different stages of disease. We will utilize innovative engineering approaches including tissue engineering and microfabrication to recreate tissue-specific pathophysiology in the context of HGSOC, and examine the impact of variations in ECM composition and architecture on cellular behaviors. Through these experiments in combination with computational/statistical analysis, we will determine which of the many changes that we identify are causative for disease progression. The models we develop will have a transformative impact on the study of HGSOC, and the lessons learned from our process can be applied broadly towards the larger goal of developing pathophysiologically-relevant models of all cancer types.