# Guanylin GUCY2C axis in Colorectal Cancer Initiation

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $357,970

## Abstract

PROJECT SUMMARY/ABSTRACT
Mutations in APC (~85%) or β-catenin (~5%) initiate >90% of sporadic colorectal cancers. These mutations
produce β-catenin accumulation and nuclear translocation, activating Tcf which drives transcriptional programs
underlying tumorigenesis. GUCY2C is the intestinal receptor for the hormone guanylin expressed in
colorectum. In the healthy state, guanylin-GUCY2C signaling regulates homeostatic processes that organize
the crypt-surface axis, in part through an unknown mechanism which blocks β-catenin accumulation. Of
significance, guanylin is the most commonly lost mRNA transcript in colorectal cancer. Hormone loss, which
silences GUCY2C, occurs at the earliest stages of transformation through an unknown mechanism conserved
in mice and humans. Preliminary studies reveal that guanylin loss is mediated by mutant APC-β-catenin-Tcf
signaling. Moreover, transgenic guanylin expression eliminated carcinogen-induced tumor formation in
mice. Based on these observations, we propose that mutant APC-β-catenin-Tcf signaling transcriptionally
silences guanylin as an obligatory step in tumorigenesis because guanylin-GUCY2C signaling blocks β-catenin
accumulation required for transformation. The correlative chemoprevention hypothesis suggests that guanylin
replacement should eliminate tumorigenesis driven by APC-β-catenin signaling. Here, the Pathophysiologic
Aim will identify the transcriptional mechanisms mediating guanylin loss by mutant APC-β-catenin-Tcf. These
studies will establish a novel molecular link between mutant APC-β-catenin-Tcf signaling, guanylin
suppression, and GUCY2C silencing which is obligatory for tumorigenesis. The Mechanistic Aim tests the
hypothesis that guanylin is lost because GUCY2C blocks β-catenin accumulation required for tumorigenesis.
These studies will demonstrate that the guanylin-GUCY2C axis restricts β-catenin accumulation by blocking
protein translation (synthesis) and inducing proteosomal degradation. The Prevention Aim tests the
hypothesis that colorectal cancer reflects suppression of guanylin expression and GUCY2C signaling which
can be overcome by hormone replacement. These studies will demonstrate the ability of transgenic guanylin
expression to repair oncogenic β-catenin signaling, reconstitute endogenous GUCY2C hormone expression,
and prevent tumorigenesis following biallelic APC inactivation in mice. Together, these studies will reveal a
previously unanticipated required step in colorectal cancer initiation involving guanylin loss and GUCY2C
silencing. They will shift the pathophysiological paradigm for colorectal cancer from a disease of irreversible
gene mutations to one of reversible hormone insufficiency. Mechanistically, they will identify a unique
vulnerability at the apex of the oncogenic cascade in which β-catenin-dependent events required for
tumorigenesis can be overcome by GUCY2C signaling. Moreover, they will establish the proof of principle
that colorectal cancer can be prevented ...

## Key facts

- **NIH application ID:** 9852430
- **Project number:** 5R01CA204481-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Scott A. Waldman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,970
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852430

## Citation

> US National Institutes of Health, RePORTER application 9852430, Guanylin GUCY2C axis in Colorectal Cancer Initiation (5R01CA204481-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852430. Licensed CC0.

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