食管癌发生的单细胞多阶段空间演化图谱。

Single-cell multi-stage spatial evolutional map of esophageal carcinogenesis.

作者信息

Chang Jiang, Lu Junting, Liu Qingyi, Xiang Tao, Zhang Shaosen, Yi Yonglin, Li Dongxu, Liu Tianyuan, Liu Zeyuan, Chen Xinjie, Dong Zhenghao, Li Cainan, Yi HanZhang, Yu Siqi, Huang Luwei, Qu Fangfei, Wang Mengdi, Wang Dehe, Dong Hao, Cheng Guoyu, Zhu Liang, Li Jiachen, Li Chenying, Wu Pujie, Xie Xiaoting, Teschendorff Andrew E, Lin Dongxin, Wang Xiaoqun, Wu Chen

机构信息

Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, China; Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

出版信息

Cancer Cell. 2025 Mar 10;43(3):380-397.e7. doi: 10.1016/j.ccell.2025.02.009.

DOI:10.1016/j.ccell.2025.02.009

PMID:40068596

Abstract

Cancer development involves the co-evolution of cancer cells and their surrounding microenvironment, yet the dynamics of this interaction within the physical architecture remains poorly understood. Here, we present a spatial transcriptomic map at single-cell resolution, encompassing 127 multi-stage fields of view from 43 patients, to chart the evolutionary trajectories of human esophageal squamous cell carcinoma (ESCC). By analyzing 6.4 million cells, we reveal that ESCC progression is driven by a proliferative epithelial cell subpopulation that acquires dedifferentiated and invasive characteristics. At the late precancerous stage, these cells disrupt the epithelial-stromal interface and recruit normal fibroblasts via JAG1-NOTCH1 signaling, transforming them into cancer-associated fibroblasts (CAFs). This interaction leads to the formation of a "CAF-Epi" (CAF and epithelial cell) niche at the tumor edge that shields the tumor from immune surveillance. The CAF-Epi niche formation is a key indicator of progression in ESCC and other squamous cell carcinomas and patient outcomes.

摘要

癌症发展涉及癌细胞与其周围微环境的共同进化，然而在物理结构中这种相互作用的动态过程仍知之甚少。在这里，我们展示了一个单细胞分辨率的空间转录组图谱，涵盖了来自43名患者的127个多阶段视野，以描绘人类食管鳞状细胞癌（ESCC）的进化轨迹。通过分析640万个细胞，我们发现ESCC进展由一个增殖性上皮细胞亚群驱动，该亚群获得去分化和侵袭性特征。在癌前晚期阶段，这些细胞破坏上皮-基质界面，并通过JAG1-NOTCH1信号招募正常成纤维细胞，将它们转化为癌症相关成纤维细胞（CAFs）。这种相互作用导致在肿瘤边缘形成一个“CAF-Epi”（CAF和成上皮细胞）生态位，使肿瘤免受免疫监视。CAF-Epi生态位的形成是ESCC和其他鳞状细胞癌进展以及患者预后的关键指标。