DISSECTING THE ROLE OF Β-CATENIN AND MYC IN GASTRIC TUMOR FORMATION

Tissue development, homeostasis and regeneration are remarkable processes that require the concerted activation and restriction of distinct gene-expression programs. The Wnt signaling pathway plays a prominent role in regulating the homeostasis of gastrointestinal epithelium by promoting stem cell maintenance, proliferation and cell fate specification. Aberrant activation of the Wnt/β-catenin signaling pathway occurs in the vast majority of human gastrointestinal tumors. Despite it is well known that deregulation of Wnt signaling pathway is a clear genetic event driving the onset of intestinal tumors, its role in gastric tumorigenesis remains elusive. Here, using conditional transgenic mouse models, we show that Wnt constitutive activation does not have any oncogenic effect in the gastric epithelium and cooperates with MYC in driving gastric tumorigenesis. By integrating transcriptomic and epigenomic analysis with organoid models, we provide phenotypic and mechanistic insights about how MYC and β-catenin integrate their activities in regulating stem cell function and tumor formation. Mechanistically, we reveal that MYC enhances β-catenin chromatin occupancy and Wnt-transcriptional program activation. By dissecting the MYC-dependent transcriptional program both in gastric stem cells and mouse-derived organoids, we uncover that MYC represses a large number of autophagy-related genes, resulting in the suppression of the autophagic degradation pathway. Finally, we highlight that the impairment of Epithelial Cell Adhesion Molecule (EpCAM) autophagic degradation promotes β-catenin chromatin accumulation and activation of oncogenic Wnt transcriptional program. Our work reveals an unprecedented signaling framework relevant for Wnt/Myc driven-gastrointestinal tumor development.