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

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.