The existence of heterogeneity has plunged cancer treatment into a challenging dilemma. We profiled malignant epithelial cells from 5 gastric adenocarcinoma patients through single-cell sequencing (scRNA-seq) analysis, demonstrating the heterogeneity of gastric adenocarcinoma (GA), and identified the CCKBR+ stem cell-like cancer cells associated poorly differentiated and worse prognosis. We further conducted targeted analysis using single-cell transcriptome libraries, including 40 samples, to confirm these screening results. In addition, we revealed that FOXOs are involved in the progression and development of CCKBR+ gastric adenocarcinoma. Inhibited the expression of FOXOs and disrupting cancer cell stemness reduce the CCKBR+ GA organoid formation and impede tumor progression. Mechanically, CUT&Tag sequencing and Lectin pulldown revealed that FOXOs can activate ST3GAL3/4/5 as well as ST6GALNAC6, promoting elevated sialyation levels in CCKBR+ tumor cells. This FOXO-sialyltransferase axis contributes to the maintenance of homeostasis and the growth of CCKBR+ tumor cells. This insight provides novel perspectives for developing targeted therapeutic strategies aimed at the treating CCKBR associated gastric cancer.

异质性的存在使癌症治疗陷入了一个具有挑战性的困境。我们通过单细胞测序 （scRNA-seq） 分析了 5 例胃腺癌患者的恶性上皮细胞，证明了胃腺癌 （GA） 的异质性，并确定了与低分化和预后较差相关的 CCKBR+ 干细胞样癌细胞。我们进一步使用单细胞转录组文库（包括 40 个样本）进行了靶向分析，以确认这些筛选结果。此外，我们揭示了 FOXOs 参与 CCKBR+ 胃腺癌的进展和发展。抑制 FOXOs 的表达和破坏癌细胞干性，减少 CCKBR+ GA 类器官的形成并阻碍肿瘤进展。机械上，CUT&Tag 测序和凝集素下拉显示 FOXOs 可以激活 ST3GAL3/4/5 以及 ST6GALNAC6，促进 CCKBR+ 肿瘤细胞中唾液酸水平升高。该 FOXO-唾液酸转移酶轴有助于维持体内平衡和 CCKBR + 肿瘤细胞的生长。这一见解为开发针对治疗 CCKBR 相关胃癌的靶向治疗策略提供了新的视角。