Jooske L. Monster

Abstract Cadherin-based junctions establish dynamically regulated adhesion between cells to coordinate tissue integrity and morphogenetic movements. Adhesion strength can be modulated by the organization of individual cadherin complexes into lateral clusters. Here, we identify a clustering mechanism of the cadherin complex established by its core component β-catenin.

Introduction Gastric cancer is the fifth-leading cause of cancer-related deaths worldwide, with diffuse-type gastric cancer (DGC) accounting for a third of diagnoses.1 2 For individuals with pathogenic germline variants of CDH1 or CTNNA1 at risk for developing hereditary DGC (HDGC), prophylactic gastrectomy at an early age is currently recommended.3 Resected stomachs from HDGC patients typically show multiple asymptomatic lesions confined to the gastric mucosa.

Discussion DGC progression involves the infiltration of tumour cells beyond the mucosa, which requires expansion of the population of proliferative PDCs by preventing their differentiation into SRCs. Using spatial transcriptomic profiling of HDGC lesions and a CDH1KO gastric organoid model, we demonstrate that Wnt signalling activity is a key determinant of DGC cell fate and essential to sustain an undifferentiated cellular state during tumour progression.