Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N, Nanjing Street, Shenyang, Liaoning, China.
Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning, China.
Nat Commun. 2023 Feb 14;14(1):822. doi: 10.1038/s41467-023-36310-9.
Peritoneal metastasis is the leading cause of death for gastrointestinal cancers. The native and therapy-induced ascites ecosystems are not fully understood. Here, we characterize single-cell transcriptomes of 191,987 ascites cancer/immune cells from 35 patients with/without gastric cancer peritoneal metastasis (GCPM). During GCPM progression, an increase is seen of monocyte-like dendritic cells (DCs) that are pro-angiogenic with reduced antigen-presenting capacity and correlate with poor gastric cancer (GC) prognosis. We also describe the evolution of monocyte-like DCs and regulatory and proliferative T cells following therapy. Moreover, we track GC evolution, identifying high-plasticity GC clusters that exhibit a propensity to shift to a high-proliferative phenotype. Transitions occur via the recently described, autophagy-dependent plasticity program, paligenosis. Two autophagy-related genes (MARCKS and TXNIP) mark high-plasticity GC with poorer prognosis, and autophagy inhibitors induce apoptosis in patient-derived organoids. Our findings provide insights into the developmental trajectories of cancer/immune cells underlying GCPM progression and therapy resistance.
腹膜转移是胃肠道癌症死亡的主要原因。天然和治疗诱导的腹水生态系统尚未完全了解。在这里，我们对来自 35 名有/无胃癌腹膜转移 (GCPM) 患者的 191987 个腹水癌细胞/免疫细胞的单细胞转录组进行了表征。在 GCPM 进展过程中，观察到单核细胞样树突状细胞 (DC) 的增加，这些细胞具有促血管生成作用，抗原呈递能力降低，与胃癌 (GC) 预后不良相关。我们还描述了治疗后单核细胞样 DCs 和调节性及增殖性 T 细胞的演变。此外，我们追踪 GC 的进化，确定了具有高可塑性的 GC 簇，这些 GC 簇表现出向高增殖表型转移的倾向。通过最近描述的自噬依赖性可塑性程序即早衰发生转变。两个与自噬相关的基因 (MARCKS 和 TXNIP) 标记具有较差预后的高可塑性 GC，自噬抑制剂可诱导患者来源的类器官发生细胞凋亡。我们的研究结果为 GCPM 进展和治疗耐药性的癌症/免疫细胞的发育轨迹提供了深入了解。
