# Defining the changing microbiome composition and host-microbe mechanistic effects following Apc inactivation during colorectal cancer pathogenesis

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2024 · $48,974

## Abstract

Project Summary
Globally, colorectal cancer (CRC) is the second leading cause of cancer-related deaths in men and women
and is projected to increase by 70% in the next 20 years. One of the earliest initiating events of CRC is
mutation of adenomatous polyposis coli (APC), a tumor suppressor gene. This mutation initiates the gradual
progression from normal proliferating colon epithelial cells (CECs) to dysplastic lesions, to the eventual
formation of tumors, known as adenomas. Somatic APC mutations occur in >80% of sporadic CRCs. Growing
evidence demonstrates that factors within the local microenvironment can significantly influence cancer risk
and onset. One key characteristic of the colon adenomatous environment is an imbalanced microbiome.
Disruption in the makeup of these microbiota, known as dysbiosis, is related to many diseases, including
colitis, inflammatory bowel disease, and CRC. While dysbiosis contributes to promoting adenoma progression
and CRC, whether APC mutation triggers changes in the local microenvironment to facilitate tumor progression
and microbiome dysbiosis remains largely unknown. Using an inducible murine model of CEC Apc truncation,
our lab found that Apc inactivation and subsequent colon tumorigenesis results in microbiome dysbiosis and
outgrowth of pathogenic species, further, associated with increased bacterial mucosal adherence. This
proposal aims to define the timing and mechanisms by which the early microbiome changes following Apc
inactivation. We hypothesize that Apc loss alters the microenvironment to cause early loss of commensal
species and provides a habitat for pathogenic outgrowth and pro-carcinogenesis. We will test our hypothesis
through the following aims. Aim 1: Defining the effects of Apc inactivation on the composition, spatial/temporal
dynamics, and tumorigenic potential of the host microbiome. Using 16S rRNA amplicon sequencing and
microbiology, I will identify early microbiome changes following Apc loss during gradual colon tumorigenesis
and will determine if this differs by colon region. I will use germ-free models to evaluate if the changing
microbiome is sufficient to induce colon tumorigenesis. Aim 2: Identifying the mechanism(s) by which Apc
inactivation contributes to microbiome dysbiosis and the expansion of pathogenic species. I will utilize
transcriptomics and metabolomics to examine changes in metabolic pathways and gene regulation in
association with changes in microbiome composition and timing of Apc inactivation. This research will provide
novel insights into the events occurring upon Apc mutation and the crosstalk between mutated CECs and the
local microbiome.

## Key facts

- **NIH application ID:** 10913354
- **Project number:** 5F31CA284760-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Lindsey Dzierozynski
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-09-16 → 2026-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913354

## Citation

> US National Institutes of Health, RePORTER application 10913354, Defining the changing microbiome composition and host-microbe mechanistic effects following Apc inactivation during colorectal cancer pathogenesis (5F31CA284760-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10913354. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*