Colorectal cancer is the 4th most common cancer and 2nd leading cause of cancer death. In >90% of sporadic cases, colorectal cancer initiates as mutations in APC (~85%) or its downstream degradation target, ?-catenin (~5%). These mutations result in accumulation of ?-catenin which translocates to the nucleus and regulates transcription driving epithelial dysfunction and formation of the premalignant field (adenomas). While a role for APC and ?-catenin mutations in transformation is established, gaps in knowledge reflect an incomplete understanding of the pathophysiological events linking these mutations to formation of the premalignant field, the mechanisms mediating those events, and their reversibility as a basis for cancer chemoprevention. In that context, guanylin is a paracrine peptide hormone produced by epithelial cells in the colo-rectum. Guanylin binds to GUCY2C, a receptor which maintains epithelial homeostasis by regulating proliferation, chromosomal stability, and metabolic programming, in part, by preventing ?-catenin accumulation. Recently, we revealed that guanylin loss silencing GUCY2C occurs in all colorectal tumors. Further, guanylin is lost in all adenomas, and in premalignant epithelia that precede adenoma formation. Unexpectedly, transgenic expression of guanylin (cannot be lost) in mice eliminated transformation induced by the carcinogen azoxymethane (AOM) which produces ?-catenin mutations. Based on these observations, we propose testing the novel hypothesis that that there is a reciprocal feedback loop in which nuclear signaling by mutant APC-?-catenin induces guanylin loss required for transformation because guanylin-GUCY2C blocks ?-catenin accumulation necessary for tumorigenesis. Here, the Pathophysiological Aim will test the hypothesis that guanylin loss silencing GUCY2C is required to form the premalignant field produced by mutant APC-?-catenin. These studies will demonstrate that eliminating guanylin in intestinal cells recapitulates the pathophysiology of transformation (guanylin loss mediates the disease). The Mechanistic Aim will test the hypothesis that mutant APC-?-catenin suppresses guanylin transcription because guanylin-GUCY2C blocks ?-catenin accumulation required for transformation (this molecular mechanism mediates guanylin loss). These studies will shift the paradigm in colorectal cancer from a genetic disease of irreversible APC-?-catenin mutations to a disease of reversible guanylin insufficiency. The Chemoprevention Aim will test the hypothesis that transgenic guanylin replacement blocks ?-catenin accumulation, epithelial dysfunction, and transformation induced by APC-?-catenin mutations (blocking guanylin loss prevents the disease). These studies will establish the chemoprevention paradigm that guanylin replacement eliminates intestinal transformation. In turn, these novel mechanistic insights will provide new opportunities for colorectal cancer prevention, including oral GUCY2C ligand supplementation. The potential for immediate translation is underscored by the approval of the oral GUCY2C ligand, linaclotide, to treat chronic constipation.

Public Health Relevance

This study explores a new mechanism required for the transformation of normal intestinal cells into premalignant intestinal cells. It will define the relationship between mutations in the machinery that universally contributes to intestinal transformation, and the hormone guanylin, which regulates the intestinal receptor GUCY2C. We propose that those mutations induce the formation of a premalignant field by suppressing the expression of guanylin and silencing GUCY2C, an effect which can be prevented by GUCY2C hormone replacement therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA206026-03
Application #
9479681
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Umar, Asad
Project Start
2016-05-09
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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