A High Throughput Human Tumor Modeling Technology for Cancer Drug Discovery

项目摘要 非瑟酮是一种天然存在的植物化学物质，大量存在于蔬菜和水果中作为着色剂。 临床前研究表明，非瑟酮提供抗炎和抗氧化的好处和保护 对慢性病的影响。由于其显着的好处，消费非瑟酮作为膳食补充剂 目前正在进行临床试验。根据我们最近的研究表明非瑟酮显著 下调乳腺癌细胞的致癌信号，我们假设非瑟酮具有化学预防作用， 对乳腺癌转移至关重要的过程的影响。因此，使用非瑟酮作为补充 可能对转移性进展具有预防性益处，并显著改善患者的结局。 因为乳腺癌转移通常发生在非常早期，甚至在原发性肿瘤被检测到之前， 预防促转移过程对于改善患者的结果是必不可少的。我们将测试我们的假设 使用我们的三维器官型乳腺肿瘤模型和乳腺癌的人源化小鼠模型， 研究非瑟酮对增殖、上皮向间质转化和局部增殖的化学预防作用， 癌细胞的侵袭。通过表型和机制研究，我们的目的是证明非瑟酮， 补充将对乳腺肿瘤的生长和局部和远处肿瘤的发生率有好处。 转移此外，本项目的系统研究将有助于扩大膳食营养素的研究， 补充剂作为化学预防剂以阻断乳腺癌和其他恶性肿瘤的进展。

Project Summary Fisetin is a naturally-occurring phytochemical abundantly found in vegetables and fruits as the coloring agent. Preclinical studies have shown that fisetin offers anti-inflammatory and anti-oxidant benefits and protective effects against chronic diseases. Due to its significant benefits, consumption of fisetin as a dietary supplement is currently being studied in a clinical trial. Guided by our recent studies that showed fisetin significantly downregulates oncogenic signaling in breast cancer cells, we hypothesized that fisetin has chemopreventive effects against processes that are essential to breast cancer metastasis. Thus, using fisetin as a supplement may have preventive benefits against metastatic progression and significantly improve outcomes for patients. Because breast cancer metastasis occurs often very early and even before primary tumors are detected, preventing pro-metastatic processes is essential to improve outcomes for patients. We will test our hypothesis using our three-dimensional organotypic breast tumor model and a humanized mouse model of breast cancer, to study chemopreventive effects of fisetin on proliferation, epithelial-to-mesenchymal transition, and local invasion of cancer cells. Through phenotypic and mechanistic studies, we aim to demonstrate that fisetin supplementation will have benefits against breast tumor growth and frequencies of local and distant metastasis. In addition, our systematic studies in this project will help broaden investigations of dietary supplements as chemopreventive agents to block progression of breast cancer and other malignancies.