Colorectal cancer (CRC) is one of the leading causes of cancer death. Quantitative assessment of host-gut microbiome crosstalk is important in CRC researches because impaired microbial population (dysbiosis) dominated by detrimental pathobionts such as Fusobacterium nucleatum often leads to the initiation of CRC (tumorigenesis) in genetically susceptible individuals. Development of a patient-specific tumor-microbiome model is also important because microbial signature in the colon is a potent identifier for CRC screening, suggesting the diagnostic and therapeutic potential. However, current CRC models are challenged to reflect heterogeneous genetic mutations, microbial dysbiosis, and robust co-culture necessary to demonstrate tumor- microbiome crosstalk. Developing a modular patient-specific CRC model that can quantitatively assess molecular and cellular characteristics of tumor-microbiome crosstalk germane to CRC is a critical unmet need. The overall goal is to develop a pathomimetic, patient-specific colorectal cancer-on-a-chip (CRC Chip) to quantitatively assess host-microbiome interactions germane to CRC pathophysiology and tumorigenesis. Our design strategy is to improve the current in vitro culture models by integrating gut-on-a-chip microsystem and biopsy-derived, three-dimensional (3D) colon organoid (colonoid) culture. The lumen-lamina propria (LP)- capillary tissue interface will enable to recreate an anoxic-oxic gradient at steady-state in the lumen-vascular layers. We will quantitatively visualize tumorigenic intercellular crosstalk under peristalsis-like dynamics.
We aim to build ?in vitro cohort avatars? from CRC patient cohorts with four race/ethnicities and the gender difference. Once the system is fully developed, co-culture with living CRC microbiome on the 3D colonic mucosa for two weeks will allow the longitudinal assessment of tumor-microbiome crosstalks germane to tumorigenesis. We envision that the CRC Chip is a compelling platform to advance knowledge in cancer researches because it can customize the transformative potential towards the anticipated long-term applications. The successful development of a CRC Chip with accomplished quantitative milestones will enable to study the role of intra-tumor bacteria on the metabolism of cancer drugs, contribution of gut microbiome on the efficacy of cancer immunotherapy, anti-tumor effect of microbiome, validation of microbial contribution to the trigger of metastasis, and validation of a novel anti-tumor strategy such as fecal microbiota transplantation (FMT). Our CRC Chip will potentiate to define the patient-specific anti-cancer therapeutics by reflecting patient?s microbiome signature and heterogeneous genetic variations and decipher the salient role of gut microbiome on the initiation and control of CRC.
FOR PUBLIC HEALTH RELEVANCE STATEMENT We propose to develop a pathomimetic ?Human Colorectal Cancer (CRC)-on-a-chip? that employs colorectal cancer patient?s samples with diverse demographic race/ethnicity backgrounds (Asian, Black, Hispanic, and White) as well as sex difference (female vs. male) to reconstitute the patient-specific host-microbiome ecosystem and mechanically dynamic microenvironment of the human colon. We aim to build a predictive CRC model to identify the tumorigenic contribution of the CRC gut microbiome isolated from the CRC patients or a specific CRC pathobiont (e.g. Fusobacterium nucleatum) on the colonic epithelium. This approach will be particularly important to understand how and why the gut microbiome can orchestrate the host-microbiome crosstalk in response to different demographic individuals or sex. Since current animal CRC models do not reflect patient specificity, heterogeneity, genetic backgrounds, and the population of gut microbiome, it is extremely difficult to predict and quantify the intercellular host-microbiome in CRC patients. In this study, we will aim to decipher how the independent decoupling of complex interactions in the CRC Chip reflecting demographic difference, which can contribute to the Precision Medicine Initiative and propagate multiple spin-off projects to be applied to other type of cancers that the microbiome is highly associated. More importantly, recent studies suggest that the gut microbiome dramatically changes the efficacy of cancer immunotherapy or the metastasis. Thus, we believe that the understanding of host-microbiome crosstalk will be a seminal cornerstone to discover new microbiome-based anti-cancer therapeutic interventions.
