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A personalized colorectal cancer-on-a-chip for assessing tumor-microbiome crosstalk


Year of Award:
2019
Status:
Active
Award Type:
R21
Project Number:
CA236690
RFA Number:
RFA-CA-18-002
Technology Track:
Molecular & Cellular Analysis Technologies
PI/Project Leader:
KIM, HYUN JUNG
Other PI or Project Leader:
Not Applicable
Institution:
UNIVERSITY OF TEXAS, AUSTIN
Colorectal cancer (CRC) is one of the leading causes of cancer death. Quantitative assessment of host-gutmicrobiome 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-microbiomemodel 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 reflectheterogeneous genetic mutations, microbial dysbiosis, and robust co-culture necessary to demonstrate tumor-microbiome crosstalk. Developing a modular patient-specific CRC model that can quantitatively assessmolecular 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) toquantitatively assess host-microbiome interactions germane to CRC pathophysiology and tumorigenesis. Ourdesign strategy is to improve the current in vitro culture models by integrating gut-on-a-chip microsystem andbiopsy-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-vascularlayers. We will quantitatively visualize tumorigenic intercellular crosstalk under peristalsis-like dynamics. We aimto 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 twoweeks will allow the longitudinal assessment of tumor-microbiome crosstalks germane to tumorigenesis. Weenvision that the CRC Chip is a compelling platform to advance knowledge in cancer researches because it cancustomize the transformative potential towards the anticipated long-term applications. The successfuldevelopment of a CRC Chip with accomplished quantitative milestones will enable to study the role of intra-tumorbacteria on the metabolism of cancer drugs, contribution of gut microbiome on the efficacy of cancerimmunotherapy, 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 willpotentiate to define the patient-specific anti-cancer therapeutics by reflecting patient?s microbiome signature andheterogeneous genetic variations and decipher the salient role of gut microbiome on the initiation and control ofCRC.