Microfluidic Droplet Organoids to Decipher the Tumor Heterogeneity in CRC of African Ancestry

摘要 在美国，结直肠癌是第三大常见癌症，也是导致癌症死亡的第三大原因 非洲裔美国人的结直肠癌发病率高于普通人群。此外， 非洲裔美国人结直肠癌患者的存活率仍然显著低于其他种族 组。因此，非洲裔美国人的结直肠癌仍然是一种令人衰弱的疾病。 是一个尚未满足的需要，以进一步了解生物学，特别是肿瘤异质性的疾病发展 为这些患者提供新的治疗方法，以改善治疗和整体预后。在我们的 前期工作，我们开发了一种基于液滴的微流控技术来产生微型 可用于单个癌细胞生长以研究肿瘤异质性和药物的液滴有机物(MDO) 抵抗。因此，我们的总体假设是，MDO是唯一可以用来系统地 从功能和基因组两方面研究肿瘤的异质性。我们现在建议通过1)来检验我们的假设 从非洲血统的结直肠癌患者中产生微型液滴有机物(MDO)，以便执行 高通量药物筛选以研究肿瘤的异质性和2)系统地表征表观基因组 克隆的CRC MDO群体，并将其与肿瘤生长的异质性和对 心理治疗。总之，这些研究将朝着理解肿瘤异质性的顺序迈出重要的一步。 开发和验证非洲裔美国人结直肠癌患者的新的有效疗法，这些疗法可以 成功地将其移植到诊所。

Abstract Colorectal cancer is the third most common cancer and the third leading cause of cancer deaths in the US and the incidence of colorectal cancer in African Americans is higher than the general population. Furthermore, survival among African American patients with colorectal cancer remains significantly lower than other racial groups. Therefore, colorectal cancer in African American patients still remains a debilitating disease and there is an unmet need to further understand the biology and specifically tumor heterogeneity of this disease to develop new therapeutic approaches for these patients in order to improve treatment and overall prognosis. In our preliminary work, we have developed a droplet-based microfluidics based technology to generate miniature droplet organoids (MDO) that can be used to grow single cancer cells to study tumor heterogeneity and drug resistance. Thus, our overall hypothesis is that MDO is the only method that can be used to systematically study tumor heterogeneity both functionally and genomically. We now propose to test our hypothesis by 1) Generating miniature droplet organoids (MDO) from patients of African ancestry with CRC in order to perform high-throughput drug screens to study tumor heterogeneity and 2) Systematically characterize the epigenomes of the clonal CRC MDO populations and associate them with tumor growth heterogeneity and resistance to therapy. In summary, these studies will take important steps toward understanding tumor heterogeneity in order to develop and validate new and potent therapies in African American colorectal cancer patients that can be successfully translated into the clinic.