Silencing of the GUCY2C Tumor Suppressor by Oncogenic Beta Catenin is an Obligatory Step in Colorectal Tumorigenesis

Colorectal cancer is the second leading cause of cancer death. Intestinal transformation begins near‐universally with activation of Wnt signaling through mutations in APC (80%) or its degradation target β‐catenin (15%), producing a gain‐of‐function in TCF‐dependent nuclear transcription underlying epithelial dysfunction and tumorigenesis. While a role for APC and β‐catenin in colorectal cancer is well‐established, steps leading from gene mutation to tumorigenesis, and their reversibility, remain incompletely defined. Guanylin is the paracrine hormone in the colorectum for the receptor GUCY2C. This hormone is the most commonly lost gene product in colorectal cancer, and its universal suppression and associated silencing of GUCY2C at the earliest step in neoplasia contributes to tumorigenesis in a mechanism that is conserved across species. GUCY2C regulates homeostatic mechanisms organizing the intestinal crypt‐surface axis, and its silencing through guanylin suppression drives hyperproliferation, DNA damage, metabolic reprogramming and desmoplasia contributing to tumorigenesis. Recently, we demonstrated that inactivation of APC, or activation of β‐catenin, induces TCF‐dependent elimination of guanylin transcription and translation in human intestinal cells in vitro and in conditional genetic mouse models in vivo. Conversely, activation of GUCY2C induces cGMP protein kinase‐dependent elimination of wild type or mutant β‐catenin by amplifying proteosomal degradation, even in the context of mutations which inactivate the APC degradation complex. Importantly, enforced genetic expression of guanylin in intestinal epithelial cells completely eliminated tumorigenesis in all mouse models of colorectal cancer examined. These observations reveal for the first time a mechanism through which GUCY2C is silenced in colorectal tumorigenesis, and present a pathophysiologic model in which mutant APC‐β‐catenin signaling eliminates guanylin expression as an obligatory step in tumorigenesis. This GUCY2C silencing removes an essential block to transformation, creating a circuit which amplifies mutant APC‐β‐catenin signaling. These studies shift the prevailing paradigm for colorectal tumorigenesis from an irreversible oncogenomic mechanism to a reversible functional mechanism whose reconstitution abrogates those mutational defects. In that context, this disease‐specific vulnerability can be leveraged to eliminate tumorigenesis by GUCY2C hormone replacement. We have translated these observations to an NCI‐funded clinical program exploring the utility of oral GUCY2C ligands to prevent colorectal cancer. Support or Funding Information Support was provided by grants from the National Institutes of Health (NIH; P30 CA56036, R01 CA170533), the Pennsylvania Department of Health (SAP 4100059197, SAP 4100051723), and Targeted Diagnostics & Therapeutics. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. J.E.L. was supported by NIH institutional award T32 GM08562 for Postdoctoral Training in Clinical Pharmacology and is the recipient of the Young Investigator Award from the American Society for Clinical Pharmacology and Therapeutics. E.S.B. is the recipient of the Ruth L. Kirschstein National Research Service Award for Individual Predoctoral MD/PhD Fellows (1 F30 CA180500) from the NIH. S.A.W. is the Samuel MV Hamilton Professor of Thomas Jefferson University.