Divergent lineage trajectories and genetic landscapes in human gastric intestinal metaplasia organoids associated with early neoplastic progression.

Abstract

<p>Gastric intestinal metaplasia (IM) represents a critical pre-cancerous stage, characterized by a morphological spectrum that is currently inadequately represented by human cell line models. Understanding the progression of IM along the cancer spectrum is pivotal in early detection, prevention and treatment of gastric cancer. However, the lack of suitable cell models for IM has hindered our understanding of its pathogenesis and neoplastic progression.</p><p>To address this significant gap, we have successfully generated a large cohort of human gastric IM organoids (IMOs) that closely recapitulate the cellular and molecular features of IM in vivo. Leveraging the power of single-cell RNA sequencing (scRNA-seq), we comprehensively characterized the stem/progenitor populations within these IMOs and delineated their lineage trajectories. Our analysis showed that lineage plasticity in IM goes beyond gastric or intestinal fates and demonstrated a reversion to a fetal phenotype. We observed that IMO cells spanned a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation, and uncovered lineage trajectories that connected different cycling and quiescent stem and progenitors, highlighting their differences in the gastric to IM transition. Lastly, we found that cell populations in gastric IM and cancer tissues were highly similar to those derived from IMOs and exhibited a fetal signature.</p><p>In conclusion, our findings provide crucial insights into the lineage trajectories and genetic landscapes of IM, demonstrating that our IM organoid models are ideal for studying early gastric neoplastic transformation and chemoprevention. This research advances our understanding of IM pathogenesis and its neoplastic progression, potentially paving the way for the future development of targeted therapeutic strategies and improved patient outcomes.</p>