Elucidating GUT microbiota-driven tuft-2 cell expansion as a risk factor for neoplastic adenoma development in early-onset CRC among black US residents - young (< 50 years) individuals with african…

The National Cancer Institute of the Department of Health and Human Services awarded Cleveland Clinic Lerner College of Medicine of Case Western Reserve University $543,757 on September 3, 2026, under the Cancer Biology Research program (CFDA 93.396) to investigate gut microbiota-driven tuft-2 cell expansion as a biomarker for aggressive adenoma formation in early-onset colorectal cancer among Black US residents.

The project tests the hypothesis that gut microbiota from early-onset colorectal cancer patients drives distinct tuft-2 cell expansion trajectories that exacerbate adenoma development, particularly in patients with African ancestry compared to white patients. The research uses gnotobiotic and APC/MIN+ mouse models to establish causality between microbiota composition and neoplastic adenoma formation, with the goal of developing molecular mechanisms and clinical strategies to reduce ancestry-based disparities in colorectal cancer burden. Two specific aims address tuft-2 cell expansion trajectories induced by patient-derived microbiota and the direct impact of microbiota-driven expansion on adenoma development.

Performance occurs in Cleveland, Ohio. The award obligates $543,757 for the five-year project period through August 31, 2031. This is a Project Grant (assistance type R37).

Elucidating GUT microbiota-driven tuft-2 cell expansion as a risk factor for neoplastic adenoma development in early-onset CRC among black US residents - young (< 50 years) individuals with african ancestry have a higher rate of early-onset colorectal cancer (EOCRC) than older individuals of african ancestry and white patients in the US. This is because they are at a greater risk of metachronous adenoma formation, which develops in the same location after surgical removal of initial polyps. Despite advances in CRC screening, there are still no clinical biomarkers to predict the formation of aggressive metachronous adenomas in the colon. Our long-term goal is to accelerate the development of microbiota-driven tuft-2 cell expansion as a clinical and cellular biomarker for predicting aggressive adenoma formation in EOCRC. The overall objectives of this proposal are to determine the mechanisms by which GUT microbiota-driven tuft-2 cell expansion affects adenoma formation in EOCRC patients and to examine how this impact varies across genetic ancestries. The central hypothesis is that GUT microbiota-driven tuft-2 cell expansion exacerbates adenoma development in EOCRC patients with african ancestry compared to white EOCRC patients. The rationale for this project is that a determination of molecular mechanisms by which GUT microbiota-driven tuft-2 cell expansion accelerates adenoma development in EOCRC patients with african ancestry is likely to offer a strong scientific framework whereby new strategies to reduce genetic ancestry-based differential clinical burden can be developed. The central hypothesis will be tested by pursuing two specific aims: 1) to test the hypothesis that GUT microbiota from EOCRC patients causes distinct tuft-2 cell expansion trajectories; and 2) to test the hypothesis that GUT microbiota-driven tuft-2 cell expansion exacerbates adenoma formation in EOCRC patients. Gnotobiotic and APC/min+ mouse models are necessary to rigorously establish causality and account for native stromal and immune interactions in a physiologically intact system that cannot be captured by in vitro models alone. Under the first aim, fecal microbiota from EOCRC patients will be transplanted into the colon of these mouse models to analyze the impact of GUT microbiota on inter and intracellular communication using single-cell omics. For the second aim, colonic organoids will be cultured with the supernatant of microbiota-activated tuft- 2 cells. The research proposed in this application is innovative as IT focuses on the microbiota-driven expansion of tuft-2 cells associated with an increase in adenoma precursor cells. The proposed research is significant because IT is expected to provide strong scientific justification for future translational studies focused on the normal-adenoma-carcinoma sequence in CRC. Ultimately, such knowledge has the potential to offer new opportunities to develop innovative therapies to reduce the genetic ancestry-associated differential clinical burden in EOCRC.