Deciphering the Role of Gut Microbiome in Colitis-Associated Colorectal Cancer Using a Patient-Specific Disease-on-a-Chip

项目摘要/摘要 结肠炎相关癌(CAC)是指炎症性肠病(IBD)向 结直肠癌(CRC)越来越多的证据表明，细胞间的异常串扰 肠道微生物群和炎性宿主细胞与CAC的发生发展密切相关。因此，映射 微生物特征和上皮可塑性对宿主-微生物组细胞间串扰的响应是至关重要的。 从机制上破译肠道微生物群在CAC致病中的作用。然而，目前的动物 模型既没有反映CAC患者的异质性遗传变异，也没有定量地可视化宿主- 微生物组在时空上的分子串扰。体外共培养模型缺乏长期稳定性 进行纵向的宿主-微生物组研究，这是研究病理细胞间的必要的 相声。因此，开发一种针对患者的CAC模型可以定量评估细胞和 宿主-微生物组串扰的分子特征是描绘病理性宿主-肠道的一个关键的未得到满足的需求 微生物群串扰及其在CAC中的原因和后果。规划的长期目标 研究是开发具有变革性和可实施性的癌症工程模型系统，该系统包括 癌症-微生物群的串音。在这项拟议研究的F99阶段，针对患者的芯片上CAC 该模型将利用尖端的人体芯片器官技术进行开发。肠道的影响 将利用该模型系统研究CAC发展过程中的微生物群。在K00阶段，单人- 细胞分析和多组学方法将被纳入到个性化CAC模型中，以获得更高的 对确定的宿主的潜在分子和细胞机制的解析和全面研究 微生物组细胞间的相互作用。通过绘制癌症和微生物群之间的串扰图，复杂 癌症病理生物学将被解剖和操纵，以回答紧迫的问题。

Project Summary/Abstract Colitis-associated cancer (CAC) refers to the pathological transition from inflammatory bowel disease (IBD) to colorectal cancer (CRC). Burgeoning evidence suggests that the abnormal intercellular crosstalk between the gut microbiome and inflammatory host cells is highly associated with the development of CAC. Thus, mapping the microbial signature and epithelial plasticity in response to the host-microbiome intercellular crosstalk is critical to mechanistically decipher the role of gut microbiome on the CAC pathogenicity. However, current animal models neither reflect the heterogeneous genetic variants in CAC patients nor quantitatively visualize host- microbiome molecular crosstalk in a spatiotemporal manner. In vitro co-culture models lack the long-term stability to perform a longitudinal host-microbiome study that is necessary to investigate the pathological intercellular crosstalk. Hence, developing a patient-specific CAC model that can quantitatively assess the cellular and molecular signature of host-microbiome crosstalk is a critical unmet need to map the pathological host-gut microbiome crosstalk and unravel their cause vs. consequence in CAC. The long-term goal of the outlined research is to develop transformative and implementable engineered cancer model systems that encompass cancer-microbiome crosstalk. In the F99 phase of this proposed research, a patient-specific CAC-on-a-chip model will be developed by utilizing a cutting-edge human organ-on-a-chip technology. The effects of gut microbiome in the development of CAC will be investigated using this model system. In the K00 phase, single- cell analysis and multi-omics approach will be incorporated into the personalized CAC model for a higher resolution and comprehensive study of the underlying molecular and cellular mechanism of the defined host- microbiome intercellular interactions. By mapping crosstalk between cancer and microbiome, complicated cancer pathobiology will be dissected and manipulated to answer the pressing questions.