Zhou Yong, Mo Shanlan, Cui Heyang, Sun Ruifang, Zhang Weimin, Zhuang Xiaofei, Xu Enwei, Li Hongyi, Cheng Yikun, Meng Yongsheng, Liu Meilin, Yan Ting, Liu Huijuan, Zhang Ling, Yang Bin, Xi Yanfeng, Wang Shubin, Cheng Xiaolong, Li ShuaiCheng, Liu Zhihua, Zhan Qimin, Hu Zheng, Cui Yongping
Cancer Institute, Department of Pathology, Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518000, China.
Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan 030001, China.
Natl Sci Rev. 2024 Apr 23;11(5):nwae150. doi: 10.1093/nsr/nwae150. eCollection 2024 May.
Esophageal squamous cell carcinoma (ESCC) is a poor-prognostic cancer type with extensive intra- and inter-patient heterogeneity in both genomic variations and tumor microenvironment (TME). However, the patterns and drivers of spatial genomic and microenvironmental heterogeneity of ESCC remain largely unknown. Here, we generated a spatial multi-omic atlas by whole-exome, transcriptome, and methylome sequencing of 507 tumor samples from 103 patients. We identified a novel tumor suppressor , accounting for 22% of ESCCs with frequent somatic mutations or hyper-methylation, which promoted migration and invasion of ESCC cells . Analysis of the TME and quantification of subclonal expansion indicated that ESCCs undergo spatially directed evolution, where subclones mostly originated from the tumor center but had a biased clonal expansion to the upper direction of the esophagus. Interestingly, we found upper regions of ESCCs often underwent stronger immunoediting with increased selective fitness, suggesting more stringent immune selection. In addition, distinct TMEs were associated with variable genomic and clinical outcomes. Among them, hot TME was associated with high immune evasion and subclonal heterogeneity. We also found that immunoediting, instead of CD8 T cell abundance, acts as an independent prognostic factor of ESCCs. Importantly, we found significant heterogeneity in previously considered potential therapeutic targets, as well as BRCAness characteristics in a subset of patients, emphasizing the importance of focusing on heterogeneity in ESCC targeted therapy. Collectively, these findings provide novel insights into the mechanisms of the spatial evolution of ESCC and inform precision therapeutic strategies.
食管鳞状细胞癌（ESCC）是一种预后较差的癌症类型，在基因组变异和肿瘤微环境（TME）方面，患者内部和患者之间均存在广泛的异质性。然而，ESCC空间基因组和微环境异质性的模式及驱动因素仍 largely未知。在此，我们通过对103例患者的507个肿瘤样本进行全外显子组、转录组和甲基化组测序，生成了一个空间多组学图谱。我们鉴定出一种新的肿瘤抑制因子，在22%的ESCC中频繁发生体细胞突变或高甲基化，它促进了ESCC细胞的迁移和侵袭。对TME的分析和亚克隆扩增的定量表明，ESCC经历了空间定向进化，其中亚克隆大多起源于肿瘤中心，但在食管向上方向有偏向性的克隆扩增。有趣的是，我们发现ESCC的上部区域通常经历更强的免疫编辑，具有更高的选择适应性，表明免疫选择更为严格。此外，不同的TME与可变的基因组和临床结果相关。其中，热TME与高免疫逃逸和亚克隆异质性相关。我们还发现免疫编辑而非CD8 T细胞丰度是ESCC的独立预后因素。重要的是，我们发现在先前认为的潜在治疗靶点以及一部分患者的BRCAness特征中存在显著异质性，强调了在ESCC靶向治疗中关注异质性的重要性。总体而言，这些发现为ESCC的空间进化机制提供了新见解，并为精准治疗策略提供了依据。
