# The Role of CCL11 in Inflammatory and Sporadic Colorectal Cancer.

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

With more than 3 million Americans affected, inflammatory bowel disease (IBD) causes significant morbidity and
can progress to colorectal cancer (CRC). There are two main forms of IBD: ulcerative colitis (UC) and Crohn’s
disease, and the associated abnormal immune response continues to be investigated with the hope that new
therapeutics can be developed. CRC is the 3rd most common cancer and 2nd leading cause of death in men and
women combined and colitis-associated cancer (CAC) is a subset of CRC. Sporadic CRC is also a major clinical
problem in Veterans. We have previously shown in a prospectively collected cohort of adult UC patients, CCL11,
classically described as an eosinophil chemoattractant, was the only analyte increased in both serum and tissue
compared to non-IBD controls. Ccl11-deficient mice have been shown to be protected from colitis in an acute
dextran sulfate sodium (DSS)-induced colitis model. However, acute colitis studies in mice lacking eosinophils
(including ΔdblGATA mice) have been mixed, suggesting it is not simply just decreased tissue eosinophil
infiltration leading to improvement in colitis. We have reported that Ccl11-deficient mice exhibit decreased tumor
number and burden in the azoxymethane (AOM)-DSS CAC model. CCL11 has also been shown to be increased
in sporadic CRC. We have now found that 1) mice with epithelial cell-specific loss of CCL11 (Ccl11∆GIepi) exhibit
decreased tumor number and burden in the AOM-DSS model; 2) tumors from CDX2P-CreERT2Apcfl/fl mice (CRC
model due to altered adenomatous polyposis coli (Apc) expression) exhibit increased CCL11 expression; 3)
epithelial cell-specific loss of CCL11 in CDX2P-CreERT2Apcfl/flCcl11fl/fl mice leads to decreased tumor number
and burden; 4) tumorigenesis is not altered in ΔdblGATA mice in the AOM-DSS model or in CDX2P-
CreERT2Apcfl/flΔdblGATA mice, 5) human colonoids express receptors for CCL11; 6) recombinant CCL11
(rCCL11) leads to decreased colonic epithelial wound restitution; and 7) tumors from Ccl11∆GIepi mice exhibit
decreased levels of pERK1/2 indicative of MAPK activation, which is frequently implicated in CRC development.
We propose to investigate the role of epithelial-derived CCL11 in oncogenic epithelial dysfunction in models of
CAC and sporadic CRC. We will use Veteran patient-derived colon tissues and organoids to validate our animal
studies and develop rationales for future human studies. Our Hypothesis is: CCL11 dysregulates epithelial
function and supports carcinogenesis via MAPK/ERK signaling in inflammatory and sporadic colon
cancer. The Specific Aims are: 1. To test the hypothesis that CCL11 activates MAPK/ERK signaling
predisposing to CAC via epithelial dysfunction. Ccl11∆GIepi and ΔdblGATA mice exposed to AOM-DSS will
be used to test the hypothesis that CCL11 leads to epithelial dysfunction via MAPK/ERK signaling in murine
models and organoids. 2. To test the hypothesis that CCL11 signaling promotes sporadic CRC driven by
somatic mutations vi...

## Key facts

- **NIH application ID:** 11136366
- **Project number:** 5I01CX002662-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Lori A Coburn
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11136366

## Citation

> US National Institutes of Health, RePORTER application 11136366, The Role of CCL11 in Inflammatory and Sporadic Colorectal Cancer. (5I01CX002662-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11136366. Licensed CC0.

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