# Pathogenesis of Early Onset Colorectal Cancer: Microbiome Contributions and Mechanisms

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $439,679

## Abstract

ABSTRACT
Early onset colorectal cancer (EO-CRC), defined as disease onset in individuals younger than 50 years, is an
emerging, deadly public health threat in the United States. Because the colon contains a densely populated
microbial ecosystem, it is hypothesized that the intimate association of colonic epithelial cells with the microbiota
can contribute to the initiation and/or progression of human CRC. However, as yet, no studies investigating the
microbiota/microbiome of patients with EO-CRC have been reported. Our group has identified that colon mucus-
invasive bacterial biofilms are common on CRCs occurring in those older than 50 (termed late onset CRC, LO-
CRC). We have demonstrated that LO-CRC-associated bacterial biofilms induce colon tumors in susceptible
mouse models. Further, our preliminary data now support that biofilms are common on EO-CRC. Herein, we will
test the hypothesis that individuals with EO-CRC display microbial and colonic epithelial signatures that differ
from age-matched controls. In our distinct, but complementary, Specific Aims, we will trace the epidemiology of
biofilm formation on CRCs for the past 35 years, test the antibody responses of EO-CRC patients and comparator
disease and control groups to biofilm and other microbes and determine if microbial exposures induce changes
in colon epithelial biology that lower the threshold for colon epithelial cell neoplastic transformation. Using
retrospective and prospective human cohorts, our Specific Aims are: 1) to determine the longitudinal association
of biofilm structure and composition with EO-CRC defined by all bacterial and multiprobe fluorescent in situ
hybridization (FISH) and 16S rRNA amplicon sequencing; 2) to characterize the binding of serum antibodies of
EO-CRC patients to a broad array of environmental organism-associated antigens (e.g., viral, phage, biofilm
bacterial and/or bacterial toxin) via programmable phage display-based profiling (known as PhIP-Seq); and 3) to
define the molecular signatures of normal EO-CRC epithelium with known biofilm status through genome-wide
methylation studies and the environmental stress responses of normal human colonoids derived from EO-CRC,
LO-CRC and healthy persons. Our results will provide insight into the microbial associations and colon epithelial
cell mechanisms that we predict potentiate EO-CRC, with the ultimate goal of informing and accelerating novel
strategies for EO-CRC detection, prevention and intervention.

## Key facts

- **NIH application ID:** 10899576
- **Project number:** 5R01CA264217-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** CYNTHIA SEARS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $439,679
- **Award type:** 5
- **Project period:** 2021-09-23 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899576

## Citation

> US National Institutes of Health, RePORTER application 10899576, Pathogenesis of Early Onset Colorectal Cancer: Microbiome Contributions and Mechanisms (5R01CA264217-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10899576. Licensed CC0.

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