The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets

Abstract

Zacarías-Fluck, et al identify and validate the Wnt receptor Fzd9 as a key effector of Myc-Wnt signaling cross-talk in a mouse model of Myc-driven pancreatic insulinomas. The huge cadre of genes regulated by Myc has obstructed the identification of critical effectors that are essential for Myc-driven tumorigenesis. Here, we describe how only the lack of the receptor Fzd9, previously identified as a Myc transcriptional target, impairs sustained tumor expansion and β-cell dedifferentiation in a mouse model of Myc-driven insulinoma, allows pancreatic islets to maintain their physiological structure and affects Myc-related global gene expression. Importantly, Wnt signaling inhibition in Fzd9-competent mice largely recapitulates the suppression of proliferation caused by Fzd9 deficiency upon Myc activation. Together, our results indicate that the Wnt signaling receptor Fzd9 is essential for Myc-induced tumorigenesis in pancreatic islets.