# Wnt signaling in obesity-associated colorectal cancer

> **NIH NIH R37** · DUKE UNIVERSITY · 2022 · $368,288

## Abstract

Project Summary
Obesity affects 42% of the U.S. population and is a major risk factor for the development of colorectal cancer.
Obese colorectal cancer patients have a five-fold increased risk of death compared to normal weight
counterparts. However, the mechanisms by which obesity increases colorectal cancer progression and
metastasis are poorly understood, which limits the development of effective prevention and treatment
strategies for colorectal cancer in obese individuals. The vast majority of colorectal cancers are initiated by loss
of the tumor suppressor gene Apc in colonic stem cells, and subsequent activation of the Wnt signaling
pathway. Wnt signaling is also required for maintenance of advanced colorectal cancers and metastases.
Research from our group demonstrates that diet-induced obesity markedly upregulates Wnt signaling in
intestinal and colonic stem cells by promoting a peroxisome proliferator-activated receptor delta (PPAR-d)
transcriptional program, which in turn increases cancer development. These findings suggest that inhibition of
Wnt signaling is a highly attractive therapeutic strategy for obesity-associated colorectal cancer. We and others
have demonstrated that colon tumors are maintained by Lgr5+ cancer stem cells, and single cell RNA
sequencing data from our lab shows that these cells are Wnt-active, while non-cancer stem cells are Wnt-low.
However, development of Wnt inhibitors to treat Apc-deficient cancers or to target cancer stem cells has
proven elusive. Rac1-GTP, a member of the Rho family of GTPases, is an intracellular transducer that
promotes Wnt signaling by mediating nuclear translocation of beta-catenin. Prex1 is a Rac-specific Rho
GTPase guanine nucleotide exchange factor that activates Rac1 by facilitating the exchange of GTP to GTP.
We found that Prex1 and active Rac1-GTP are highly enriched in intestines and colon cancers of mice treated
with high fat diet or an agonist of PPAR-d. Loss of Rac1 signaling markedly reduces intestinal tumor initiation
by inhibiting Wnt activation. Our long-term goal is to understand mechanisms of Wnt activation in colorectal
cancer and to develop new treatment strategies for this disease. Here, we hypothesize that Prex1-dependent
Rac1-GTP activity mediates obesity-induced tumorigenesis by inducing Wnt signaling in Lgr5+ cancer stem
cells. In Aim 1, we will determine the role of Prex1 signaling in high fat diet and PPAR-d-mediated intestinal
stem cell regeneration and tumor initiation. In Aim 2, we will determine the function of the Prex1 / Rac1-GTP
signaling axis in high fat diet and PPAR-d-dependent colorectal cancer stem cell function. In Aim 3, we will
identify the role of PPAR-d transcriptional targets in colorectal cancer stem cell function in the setting of diet-
induced obesity. The goal of this proposal is to identify mechanisms by which obesity-induced Wnt signaling
promotes colorectal cancer progression. Our studies will provide preclinical rationale for clinical...

## Key facts

- **NIH application ID:** 10445874
- **Project number:** 1R37CA259363-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Jatin Roper
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $368,288
- **Award type:** 1
- **Project period:** 2022-05-23 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445874

## Citation

> US National Institutes of Health, RePORTER application 10445874, Wnt signaling in obesity-associated colorectal cancer (1R37CA259363-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10445874. Licensed CC0.

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