Tumour-intrinsic alterations and stromal matrix remodelling promote Wnt-niche independence during diffuse-type gastric cancer progression

Abstract

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 during DGC progression that converge on Wnt signalling, allowing tumour cells to remain in an undifferentiated state as they disseminate away from the gastric stem cell niche. First, DGC cells establish a cell-autonomous source for Wnt-pathway activation through upregulated expression of Wnt-ligands and ‘secreted frizzled-related protein 2’ ( SFRP2 ) that potentiates ligand-induced Wnt signalling. Second, early tumour development is marked by extracellular matrix remodelling, including increased deposition of collagen I whose interactions with DGC cells suppress their differentiation in the absence of exogenous Wnt ligands. Conclusions Our findings demonstrate that tumour cell-derived ligand expression and extracellular matrix remodelling sustain Wnt signalling during DGC progression. These complementary mechanisms promote niche independence enabling expansion of undifferentiated DGC cells needed for the development of advanced tumours. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Normalised and averaged data of the Nanostring DSP analysis has been added as a supplementary table. Raw counts of the Nanostring DSP analysis and whole exome sequencing data are available on request.