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

Stephanie Jaeckel,Markus Kaller,Susanna Müller,Peter Jung,Sophie Boos,David Horst,Ursula Götz,Heiko Hermeking,Rene Jackstadt

doi:10.1038/s41467-018-06001-x

Abstract

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

Highlights

The gene encoding the transcription factor TFAP4/AP4 represents a direct target of the c-MYC oncoprotein
The present study shows that inactivation of Ap4 by deletion leads to decreased adenoma formation in ApcMin mice, which represent a preclinical model of familial adenomatous polyposis (FAP)9,10. mRNA profiling revealed downregulation of a large number of genes involved in Wnt/β-catenin and/or Notch signaling in Ap4-deficient adenomas of ApcMin mice and organoids derived from the epithelium of the small intestine
We determined the effect of Ap4 deficiency on adenoma formation in the intestine of ApcMin mice, which harbor an inactivating mutation in one Apc allele

Summary

Introduction

The gene encoding the transcription factor TFAP4/AP4 represents a direct target of the c-MYC oncoprotein. Expression profiling revealed that ISC signatures, as well as the Wnt/β-catenin and Notch signaling pathways are downregulated in Ap4-deficient adenomas and intestinal organoids. MRNA profiling revealed downregulation of a large number of genes involved in Wnt/β-catenin and/or Notch signaling in Ap4-deficient adenomas of ApcMin mice and organoids derived from the epithelium of the small intestine. The present study shows that inactivation of Ap4 by deletion leads to decreased adenoma formation in ApcMin mice, which represent a preclinical model of familial adenomatous polyposis (FAP). In line with these regulations, Ap4-deficient intestinal organoids and tumoroids show impaired re-growth capacities and decreased stemness. Our results establish Ap4 as a regulator of ISC and Paneth cell homeostasis and as a rate-limiting mediator of intestinal tumor initiation

Methods

Results

Conclusion