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

项目总结 本申请是为了回应被确认为非CA-CA的特殊利益通知(NOSI)而提交的 22-058。 而标准的生物学方法，如二维、体外细胞培养和体内动物模型 癌症的复杂性对于研究某些生物学问题很有用，它需要一系列连续的模型。 系统。在这项工作中，我们建议通过使用多个 创新的方法，首先表征并建立细胞外基质的仿生模型 (ECM)在肿瘤微环境中。ECM是生物仿生学中的一个关键元素，尤其对 在癌症的背景下，ECM的组成和结构随着 疾病的发展。 我们将特别关注高级别浆液性卵巢癌(HGSOC)，它与 特别差的存活率不到50%。HGSOC起源于输卵管，转移至 卵巢，然后通过腹膜扩散到大网膜和小肠等器官 肠系膜。对于HGSOC的研究有一个公认的额外的模型，而现有的模型还没有 检查了ECM组成或结构变化的影响。使用最先进的质谱仪， 成像技术和彻底的免疫组织化学分析，我们将表征不同 跨疾病不同阶段的正常组织和病变组织的ECM。我们将利用创新 包括组织工程和微制造在内的重建组织特异性的工程方法 HGSOC的病理生理学，并检查ECM组成和变化的影响 基于蜂窝行为的体系结构。通过这些实验与计算/统计相结合 分析后，我们将确定我们确定的许多变化中哪些是导致疾病进展的原因。 我们开发的模型将对HGSOC的研究和所学到的教训产生革命性的影响 从我们的过程中可以广泛地应用于开发与病理生理学相关的更大目标 所有癌症类型的模型。

PROJECT SUMMARY This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 22-058. 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.