Human gastric intestinal metaplasia organoids display genetic profiles linked with early neoplastic growth behaviour.

Abstract

<p>Gastric intestinal metaplasia (IM) is a pre-neoplastic lesion of gastric cancer, characterised by the transformation of normal gastric cells into intestinal cells. Although IM is associated with a higher risk of developing gastric cancer, a representative <em>in vitro </em>model that fully recapitulates the cellular and genetic alterations in IM remains unavailable. This limitation hinders a detailed biological characterisation of IM and restricts the development of predictive tools for assessing gastric cancer risk.</p><p>This study established a cohort of gastric IM organoids derived from 47 gastric cancer patients and conducted comprehensive molecular profiling and functional characterisation. Transcriptome analysis revealed a distinct gene expression profile for the IM organoids, which co-express gastric and intestinal lineage-specific markers. WES data analysis demonstrated a higher mutation burden in IM organoids compared to their normal counterparts, noting a frequent chromosome 20 gain. Functionally, IM organoids and normal gastric organoids with chromosomal aberrations exhibited greater cell-matrix independence than copy number neutral organoids. The spheroid assay enriched a subset of cell-matrix independent IM cells. The IM spheroids displayed increased chromosomal aberrations, along with an upregulation of intestinal-specific markers and genes associated with hypoxia and epithelial-mesenchymal transition.</p><p>In conclusion, this organoid cohort and spheroid model, encompassing genomic, transcriptomic, and clinicopathological data, serve as invaluable resources for investigating the pathways involved in IM pathogenesis and cell-matrix independence. These tools pave the way for a mechanistic understanding of the sequential changes necessary for gastric cancer progression and the future development of early detection methods and targeted therapeutic strategies.</p>