Diffuse gastric cancer emerges and evolves through selection and niche reinforcement of a BCL2-high epithelial state

ABSTRACT: Diffuse-type gastric cancer (DGC) is an aggressive malignancy, yet its earliest evolutionary trajectories—how initiating lesions interact with tissue context to determine whether nascent clones regress, remain contained, or progress—remains poorly defined. Here, using gastric epithelium–restricted Cre–loxP models integrated with adeno-associated virus (AAV)–based in vivo somatic editing, we modeled DGC development. Long-term follow-up showed that Cdh1 deletion initiated a progenitor-associated epithelial plasticity, whereas concomitant Trp53 deletion accelerated progression. Time-resolved analysis revealed that newly induced Cdh1-deleted clones underwent a proliferative burst followed by marked regression within the first month irrespective of Trp53 status; Trp53 deletion instead accelerated subsequent re-emergence of the mutant epithelial population. During regression, epithelial BMP-response activity increased. Fibroblast-derived BMP signals acting through epithelial SMAD4 promoted differentiation and restrained WNT-associated progenitor growth, accompanied by reduced BCL2 expression. During clonal re-emergence and progression, Trp53 deletion sustained epithelial OPN and CXCL5 expression, enabling escape from stromal restraint through complementary extrinsic and intrinsic mechanisms. CXCL5 recruited CXCR2⁺ granulocytic cells, which promoted fibroblast remodeling toward an inflammatory, BMP-low state and weakened the stromal barrier to clonal expansion. In parallel, OPN–CD44 signaling expanded progenitor-like tumor cells and induced BCL2 expression. Thus, reduced BMP-mediated restraint and OPN-driven survival signaling collectively established a BCL2-dependent state that enabled progenitor-like tumor cells to withstand WNT-associated proliferative stress. Pharmacological inhibition and somatic deletion of Bcl2 suppressed early tumor outgrowth in vivo. Together, these findings identify inflammatory niche-driven release of stromal restraint as a key transition in DGC progression and BCL2-dependent progenitor survival as a targetable vulnerability for early intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE316665 | GEO | 2026/09/09

REPOSITORIES: GEO