Ap4 is rate limiting for intestinal tumor formation by controlling the homeostasis of intestinal stem cells

• DOI: 10.1038/s41467-018-06001-x
• Publication Date: 2018-08-28T23:20:48Z
• Authors: Stephanie Jaeckel; Markus Kaller; Rene Jackstadt; Ursula Götz; Susanna Müller; Sophie Boos; David Horst; Peter Jung; Heiko Hermeking
• Keywords: Organoid; Homeostasis; Paneth cell; Limiting

Abstract The gene encoding the transcription factor TFAP4/AP4 represents a direct target of c-MYC oncoprotein. Here, we deleted Ap4 in Apc Min mice, preclinical model inherited colorectal cancer. deficiency extends their average survival by 110 days and decreases formation intestinal adenomas tumor-derived organoids. effects deletion are presumably due to reduced number functional stem cells (ISCs) amenable adenoma-initiating mutational events. Deletion also colonic increases Paneth cells. Expression profiling revealed that ISC signatures, as well Wnt/β-catenin Notch signaling pathways downregulated -deficient AP4-associated signatures conserved between murine human cancer samples. Our results establish rate-limiting mediator adenoma initiation, regulator cell homeostasis.