Jing Wen, Yuehua Gong, Liping Sun, Ziqi Lin, Qi Xu, 景晶晶, Lingling Hu, Hanmin Duan, Honghao Yin, Huanyu Zhang, Shixuan Shen, Nannan Dong, Yiling Li, Huakang Tu, Yuan Yuan
Early gastric carcinogenesis progresses from gastritis through intestinal metaplasia to early gastric cancer, yet the spatial origin of malignant transformation and subtype divergence remains unclear. Here we show, using spatial transcriptomics across human gastric tissues spanning disease progression, that an OLFM4-positive transitional subset emerges at the interface between gastric isthmus/glands and proliferative intestinal metaplasia crypts, consistent with an early step in intestinalization. From these crypts, transcriptional trajectories diverge toward distinct intestinal differentiation programs. Notably, proliferative crypt regions display the closest transcriptional similarity to early gastric cancer and are enriched for proliferation and DNA-repair pathways, supporting their role as a premalignant niche. We further identify increased activity of USF2-associated regulatory networks shared between crypt and cancer regions. Further stratification by Lauren subtype reveals that intestinal-type gastric cancer is characterized by a CDX2-dominated program, whereas diffuse-type gastric cancer exhibits developmental and stemness-related networks with SPP1 and CD44 co-occurring. Together, these findings highlight the intestinal metaplasia crypt as a premalignant niche and provide spatially resolved candidate markers for early detection and mechanistic investigation.