Refining the Correa cascade: Gastric stem cell plasticity, niche remodelling, and parallel pathways to neoplasia

Gastric cancer remains a leading cause of cancer mortality. The Correa cascade-stepwise progression from inflammation through atrophic gastritis, metaplasia and dysplasia to adenocarcinoma-has long defined its pathogenesis. Lineage tracing, single-cell multi-omics and organoid models now reveal marked cellular heterogeneity, plasticity and non-sequential trajectories. This review synthesises gastric stem-cell identity, niche architecture and precancerous progression. Homeostasis is sustained by cycling antral LGR5⁺ basal and IQGAP3⁺ isthmus progenitors and by quiescent corpus MIST1⁺/TROY⁺ chief-cell reserves, coordinated by Wnt/R-spondin, Notch, BMP, Hedgehog and EGFR signalling. Helicobacter pylori subverts this niche through type-IV-secretion-system delivery of cytotoxin-associated gene A and through BMP collapse, driving region-specific trajectories. In the antrum, hyperproliferation and CDX2-dependent intestinal metaplasia advance to TP53/KRAS/APC-mutant dysplasia. In the corpus, oxyntic atrophy triggers isthmus expansion via type-2 innate lymphoid cell (ILC2)-derived WNT5A and YAP signalling, alongside a tuft-cell-ILC2 interleukin-25/interleukin-13 circuit driving spasmolytic polypeptide-expressing metaplasia (SPEM). In lineage-tracing models, Kras^G12D-mutant isthmus cells can also bypass SPEM to generate dysplasia directly. Further origins include ATOH1-deficient pit cells and bone-marrow-derived epithelial hybrids. Together, these findings support a regionally stratified, stem-cell-centred model in which metaplasia and dysplasia arise as parallel cellular fates. This refinement operates at the cellular level without displacing the tissue-level Correa sequence documented in long-term human cohorts. It nominates the remodelled stem-cell niche as a tractable pharmacological target and warrants molecular profiling of at-risk progenitor populations to complement, rather than replace, histopathological surveillance.