Tumour-intrinsic alterations and stromal matrix remodelling promote Wnt-niche independence during diffuse-type gastric cancer progression
Background Development of diffuse-type gastric cancer (DGC) starts with intramucosal lesions that are primarily composed of differentiated, non-proliferative signet ring cells (SRCs). These indolent lesions can advance into highly proliferative and metastatic tumours, which requires suppression of DGC cell differentiation. Objective Our goal was to identify molecular changes contributing to the progression of indolent to aggressive DGC lesions. Design We conducted spatial transcriptomic analysis of patient tumours at different stages of hereditary DGC, comparing transcriptional differences in tumour cell populations and tumour-associated cells. We performed functional analysis of identified changes in a human gastric ( CDH1 KO) organoid model recapitulating DGC initiation. Results Our analysis reveals that distinct DGC cell populations exhibit varying levels of Wnt-signalling activity, and high levels of Wnt signalling prevent differentiation into SRCs. We identify multiple adaptations
