CCKBR+ cancer cells contribute to the intratumor heterogeneity of gastric cancer and confer sensitivity to FOXO inhibition.
Zhenya TanKe PanMinqiong SunXianzhu PanZhi YangZhiling ChangXue YangJicheng ZhuLi ZhanYakun LiuXiaofei LiKeqiong LinLin ChenHui MoWei LuoChen KanLunxi DuanHong ZhengPublished in: Cell death and differentiation (2024)
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.
Keyphrases
- single cell
- rna seq
- stem cells
- high throughput
- pet ct
- poor prognosis
- squamous cell carcinoma
- end stage renal disease
- transcription factor
- locally advanced
- ejection fraction
- signaling pathway
- newly diagnosed
- chronic kidney disease
- cancer therapy
- peritoneal dialysis
- gene expression
- prognostic factors
- radiation therapy
- long non coding rna
- binding protein
- mesenchymal stem cells
- dna methylation