# CXCR4 as a target for colon cancer chemoprevention

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2022 · $358,642

## Abstract

PROJECT SUMMARY
The risk of colorectal cancer (CRC) is substantially higher in populations consuming Western diets (WDs) and
animal models confirm this association. WD-induced tumor promotion requires epidermal growth factor receptor
(EGFR) signals that are driven by increased EGFR ligands. EGFR ligand release is controlled by proteinase
ADAM17. Colonocyte deletion or pharmacological blockade of ADAM17 suppressed tumorigenesis. Chemokine
receptor CXCR4 is expressed on colonocytes up-regulated with cancer progression and can activate ADAM17.
The role of CXCR4 in diet-promoted tumorigenesis has not been elucidated. We found that WD up-regulated
both CXCR4 and its ligand Sdf1α (aka CXCL12) in colonic mucosa. Together, these data suggest that CXCR4
is a targetable upstream regulator of WD-promoted tumor development by signaling transactivated colon
cancer cell EGFR via an ADAM17-dependent mechanism. While CXCR4 is rarely mutated in cancer, its
expression is up-regulated by transcription factors (TFs) and epigenetic changes, further evidence that factors
such as diet regulate its activity. In preliminary studies, MSX-122, a CXCR4 inhibitor well tolerated in clinical
trials, reduced colon tumor incidence by nearly 70% in azoxymethane (AOM)-treated Apc+/Min mice. Moreover,
mice deleted of colonocyte CXCR4 developed fewer tumors than CXCR4+/+ mice on an Apc-deficient
background. We hypothesize that CXCR4 is required for WD-promoted tumorigenesis, and that natural
product (NP) inhibition of CXCR4 is a promising chemopreventative strategy. Studies that dissect CXCR4
regulation and effector signals and identify novel NP inhibitors could converge to uncover new targets for CRC
prevention. To study the role of CXCR4 in tumor promotion by WDs and identify novel inhibitors, we propose
three specific aims: Aim 1 To determine if CXCR4 activity is required for WD-promoted tumorigenesis. 1a)To
assess the ability of CXCR4 inhibitor MSX-122 to suppress AOM tumorigenesis. We will compare MSX effects
in Std diet and WD in premalignant and malignant phases and assess effector signals by RNAseq and EGFR
activation. 1b) To genetically assess the role of CXCR4 in CRC, comparing colonocyte null CXCR4Δ/Δ mice to
CXCR4+/Δ and CXCR4+/+ mice (all on Apc deficient background) and measure end points described in aim 1a.
Aim 2a: To determine effects WD and neoplastic progression on TFs and histone modifications regulating Sdf1α
and CXCR4 locally using ChIP assays and assess global effects of diet and tumorigenesis using chromatin
ATAC-seq and DNA methylation by nano-5hmC-seal using organoids from conditional Apc-CXCR4 model. 5mC
and 5hmC signals discovered globally, for example, regulate local histone modifications. 2b) To assess Sdf1α-
CXCR4 gene regulation and effector signals in human colonic tumorigenesis using organoids as in 2a.
Aim 3a To screen NP libraries for CXCR4 inhibitory activity. CXCR4 reporter assays (Ca2+ transients, migration
assays and ligand-binding) will be us...

## Key facts

- **NIH application ID:** 10433941
- **Project number:** 5R01CA240710-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Bruce Marc Bissonnette
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $358,642
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433941

## Citation

> US National Institutes of Health, RePORTER application 10433941, CXCR4 as a target for colon cancer chemoprevention (5R01CA240710-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10433941. Licensed CC0.

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