An intestinal stem cell niche in <i>Apc</i> mutated neoplasia targetable by CtBP inhibition

Abstract

C-terminal binding protein 2 (CtBP2) drives intestinal polyposis in the <i>Apc</i>^<i>min</i> mouse model of human Familial Adenomatous Polyposis. As CtBP2 is targetable by an inhibitor of its dehydrogenase domain, understanding CtBP2's role in adenoma formation is necessary to optimize CtBP-targeted therapies in <i>Apc</i> mutated human neoplasia. Tumor initiating cell (TIC) populations were substantially decreased in <i>Apc</i>^<i>min</i><i>Ctbp2</i>^<i>+/-</i> intestinal epithelia. Moreover, normally nuclear Ctbp2 was mislocalized to the cytoplasm of intestinal crypt stem cells in <i>Ctbp2</i>^<i>+/-</i> mice, both <i>Apc</i>^<i>min</i> and wildtype, correlating with low/absent CD133 expression in those cells, and possibly explaining the lower burden of polyps in <i>Apc</i>^<i>min</i> Ctbp2^+/- mice. The CtBP inhibitor 4-chloro-hydroxyimino phenylpyruvate (4-Cl-HIPP) also robustly downregulated TIC populations and significantly decreased intestinal polyposis in <i>Apc</i>^<i>min</i> mice. We have therefore demonstrated a critical link between polyposis, intestinal TIC's and <i>Ctbp2</i> gene dosage or activity, supporting continued efforts targeting CtBP in the treatment or prevention of <i>Apc</i> mutated neoplasia.