# Reactivating the GUCY2C signaling axis opposes oncogenic B-catenin for cancer chemoprevention

> **NIH NIH F31** · THOMAS JEFFERSON UNIVERSITY · 2020 · $22,320

## Abstract

Colorectal cancer (CRC) is the 3rd leading cause of cancer-related death in the United States. With the current
standard of care, ~50% of patients will experience recurrence and death, highlighting the importance of
developing preventative CRC therapies. In the context of this unmet clinical need for more effective CRC
therapies, the previous discovery of a novel tumor suppressor which regulates epithelial integrity offers a
unique opportunity to advance treatment and prevention for this disease. The transmembrane receptor
guanylate cyclase C (GUCY2C) is well characterized as a key regulator of intestinal homeostasis upon
 in the APC/𝛽𝛽-catenin
activation by its paracrine hormone guanylin, the most commonly lost gene product in sporadic CRC.
 target 𝛽𝛽 -catenin
Preliminary studies revealed that suppression of guanylin occurs early on in the adenoma-carcinoma
development of CRC. These mutations lead to stabilization and accumulation of 𝛽𝛽-catenin in the nucleus which
continuum, aligning with mutations pathway. Indeed, activation of the Wnt signaling
drives epithelial dysfunction through increased TCF/LEF transcriptional activity. While APC and 𝛽𝛽 -catenin
pathway by mutations in APC (80%) or its downstream (15%) is a critical event in the
 APC/𝛽𝛽-catenin-mediated suppression of
mutations are well-defined primary transforming events in CRC, mechanisms leading from mutation to
tumorigenesis remain elusive. We hypothesize that CRC arises from a state of hormone insufficiency, initiated
elucidate mechanisms by which GUCY2C signaling reversibly regulates APC/𝛽𝛽-catenin-driven tumorigenesis,
by mutant guanylin in the colorectum, subsequently silencing the
GUCY2C tumor suppressor, leading to tumorigenesis. The ultimate, long-term goal of this project is to
signaling to the regulation of oncogenic 𝜷𝜷-catenin. Leveraging unique mouse models of CRC and intestinal
to inform the utility of GUCY2C ligand therapy in the prevention of CRC. To achieve this long-term objective,
enteroid culture, we will define the mechanisms by which GUCY2C attenuates oncogenic 𝛽𝛽-catenin. These
two specific aims are proposed. In Aim 1, we will define the molecular mechanism linking GUCY2C
results will establish GUCY2C as a critical mediator of epithelial transformation which can be targeted to
overcome irreversible mutations that underlie the development of >90% of CRC. In Aim 2, we will define CRC
activating mutations in 𝛽𝛽-catenin to explore the utility of GUCY2C ligand replacement to prevent tumorigenesis,
as a disease of hormone insufficiency that can be overcome by hormone replacement therapy. Using
tissue-specific conditional mouse models developed in our laboratory, we will induce bi-allelic APC loss or
to mitigate the risk of colorectal cancer in patients harboring APC/𝛽𝛽-catenin mutations can be appreciated in
informing a chemopreventive strategy to prevent CRC. The potential for immediate translation of these results
the context of the recent FDA-approval of the oral GU...

## Key facts

- **NIH application ID:** 9959379
- **Project number:** 5F31CA225123-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Amanda Pattison
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $22,320
- **Award type:** 5
- **Project period:** 2019-07-01 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959379

## Citation

> US National Institutes of Health, RePORTER application 9959379, Reactivating the GUCY2C signaling axis opposes oncogenic B-catenin for cancer chemoprevention (5F31CA225123-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9959379. Licensed CC0.

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