# SMAD4 regulation of colon epithelial cell inflammatory responses

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $423,501

## Abstract

Project Summary
While a number of studies have defined how inflammation arises and is maintained, much less is known about
how it is resolved. We have found that colon epithelium is key to either exacerbating or suppressing inflammation.
It is well-established that microbiota and immune cells signal to epithelial cells to increase production of
chemokines and pro-inflammatory cytokines that can accelerate inflammation, but we have found that TGFb
signaling via SMAD4 within the epithelium suppresses a pro-inflammatory transcriptional network. After
conditional Smad4 gene deletion in the adult murine colonic epithelium, we found striking evidence for increased
inflammatory signaling within the epithelial compartment concomitant with an increase in inflammatory infiltrate.
Mechanistically, TGFb1 and/or BMP2 inhibit transcriptional induction of multiple inflammatory genes by TNF, IL-
1b, or LPS treatment in mouse and human cultured colon epithelial cells. Furthermore, >75% of mice with adult-
onset deletion of the Smad4 gene in intestinal epithelium developed invasive mucinous adenocarcinomas of the
distal colon within 3 months after dextran sodium sulfate (DSS)-induced colitis, while no tumors were found
without colitis or in the SMAD4+ controls. In humans, we found a much higher incidence of SMAD4 loss in colitis-
associated carcinoma (CAC) than in sporadic colorectal cancer. Based on our observations, we hypothesize that
TGFb signaling via SMAD4 functions as a tumor suppressor, in part, through the inhibition of pro-inflammatory
cytokine responses in intestinal epithelial cells. The major goal of this research is to determine the mechanisms
by which TGFb superfamily signaling regulates colonic inflammatory responses and how this regulation is linked
to tumor suppression. We will examine our hypothesis through the following specific aims: Aim 1. Determine the
mechanism by which SMAD4-mediated signaling modulates cytokine signaling pathways in colon epithelial cells.
Working hypothesis: SMAD4-mediated signaling inhibits transcriptional responses to inflammatory stimuli in
colonic epithelial cells via specific inhibitory complexes on cytokine-induced genes. We will determine which
genes are directly regulated by SMAD4 and how this regulation alters responses to pro-inflammatory cues in
cultured cells and in vivo through a combination of RNA-seq, ATAC-seq and ChIP-seq experiments. Aim 2.
Determine how dysregulated cytokine signaling regulates tumorigenesis in Smad4 null colonic epithelium.
Working hypothesis: SMAD4-mediated suppression of epithelial inflammatory response genes is required to
prevent tumorigenesis during colitis. We propose to examine in vivo how SMAD4 regulates specific inflammation-
associated signaling pathways and gene expression and how those pathways contribute to suppression of CAC.
We will identify these regulatory pathways using single cell analytical approaches to understand the cell-specific
roles of SMAD4 within colon epith...

## Key facts

- **NIH application ID:** 10433826
- **Project number:** 5R01CA235016-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** ANNA L MEANS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,501
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433826

## Citation

> US National Institutes of Health, RePORTER application 10433826, SMAD4 regulation of colon epithelial cell inflammatory responses (5R01CA235016-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10433826. Licensed CC0.

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