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

项目总结/摘要 结肠炎相关性癌症（CAC）是指从炎症性肠病（IBD）到结肠癌的病理转变。 结直肠癌（CRC）。新兴的证据表明，细胞间的异常串扰， 肠道微生物组和炎性宿主细胞与CAC的发展高度相关。因此，映射 响应宿主-微生物组细胞间串扰的微生物特征和上皮可塑性是关键的 以机械地解释肠道微生物组对CAC致病性的作用。目前，动物 模型既不能反映CAC患者的异质性遗传变异，也不能定量地可视化宿主， 微生物组分子以时空方式串扰。体外共培养模型缺乏长期稳定性 进行纵向宿主微生物组研究，这是研究病理性细胞间 串话。因此，开发一种患者特异性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绘制病理性宿主-肠道图谱的关键未满足需求 微生物组串扰和解开他们的原因与CAC的后果。概述的长期目标 研究的目的是开发变革性和可实施的工程癌症模型系统， 癌症-微生物组串扰。在这项拟议研究的F99阶段，一种患者特异性CAC芯片， 该模型将利用尖端的人体器官芯片技术开发。肠道的影响 将使用该模型系统研究CAC发展中的微生物组。在K 00阶段，单- 细胞分析和多组学方法将被纳入个性化的CAC模型， 解析和全面研究确定的宿主的潜在分子和细胞机制- 微生物组细胞间相互作用。通过绘制癌症和微生物组之间的串扰，复杂的 癌症病理学将被剖析和操纵，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.