Li Rutao, Li Na, Yang Qianqian, Tong Xing, Wang Wei, Li Chang, Zhao Jun, Jiang Dong, Huang Haitao, Fang Chen, Xie Kai, Yuan Jiamin, Chen Shaomu, Li Guangbin, Luo Haitao, Gao Zhibo, Wu Dongfang, Cui Xiaoli, Jiang Wei, Guo Lingchuan, Ma Haitao, Feng Yu
Department of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China.
Institute of Thoracic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China.
Genome Med. 2024 Dec 18;16(1):148. doi: 10.1186/s13073-024-01422-4.
Understanding the stepwise progression of esophageal squamous cell carcinoma (ESCC) is crucial for developing customized strategies for early detection and optimal clinical management. Herein, we aimed to unravel the transcriptional and immunologic alterations occurring during malignant transformation and identify clinically significant biomarkers of ESCC.
Digital spatial profiling (DSP) was performed on 11 patients with early-stage ESCC (pT1) to explore the transcriptional alterations in epithelial, immune cell, and non-immune cell stromal compartments across regions of distinct histology, including normal tissues, low- and high-grade dysplasia, and cancerous tissues. Furthermore, single-cell spatial transcriptomics was performed using the CosMx Spatial Molecular Imaging (SMI) system on 4 additional patients with pT1 ESCC. Immunohistochemical (IHC) analysis was performed on consecutive histological sections of 20 pT1 ESCCs. Additionally, public bulk and single-cell RNA-sequencing (scRNA-seq) datasets were analyzed, and in vitro and in vivo functional studies were conducted.
Spatial transcriptional reprogramming and dynamic cell signaling pathways that determined ESCC progression were delineated. Increased infiltration of macrophages from normal tissues through dysplasia to cancerous tissues occurred. Macrophage subtypes were characterized using the scRNA-seq dataset. Cell-cell communication analysis of scRNA-seq and SMI data indicated that the migration inhibitory factor (MIF)-CD74 axis may exhibit pro-tumor interactions between macrophages and epithelial cells. DSP, SMI, and IHC data demonstrated that DTX3L expression in epithelial cells and BST2 expression in stromal cells increased gradually with ESCC progression. Functional studies demonstrated that DTX3L or BST2 knockdown inhibited ESCC proliferation and migration and decreased M2 polarization of tumor-associated macrophages.
Spatial profiling comprehensively characterized the molecular and immunological hallmarks from normal tissue to ESCC, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease and contributing to the prevention of ESCC. Within this exploration, we uncovered biomarkers that exhibit a robust correlation with ESCC progression, offering potential new avenues for insightful therapeutic approaches.
了解食管鳞状细胞癌（ESCC）的逐步进展对于制定早期检测和优化临床管理的定制策略至关重要。在此，我们旨在揭示恶性转化过程中发生的转录和免疫改变，并确定ESCC具有临床意义的生物标志物。
对11例早期ESCC（pT1）患者进行数字空间分析（DSP），以探索不同组织学区域（包括正常组织、低级别和高级别发育异常以及癌组织）上皮、免疫细胞和非免疫细胞基质区室中的转录改变。此外，使用CosMx空间分子成像（SMI）系统对另外4例pT1 ESCC患者进行单细胞空间转录组学分析。对20例pT1 ESCC的连续组织学切片进行免疫组织化学（IHC）分析。此外，分析了公开的批量和单细胞RNA测序（scRNA-seq）数据集，并进行了体外和体内功能研究。
描绘了决定ESCC进展的空间转录重编程和动态细胞信号通路。巨噬细胞从正常组织经发育异常到癌组织的浸润增加。使用scRNA-seq数据集对巨噬细胞亚型进行了表征。scRNA-seq和SMI数据的细胞间通讯分析表明，迁移抑制因子（MIF）-CD74轴可能在巨噬细胞和上皮细胞之间表现出促肿瘤相互作用。DSP、SMI和IHC数据表明，上皮细胞中的DTX3L表达和基质细胞中的BST2表达随着ESCC进展而逐渐增加。功能研究表明，DTX3L或BST2敲低可抑制ESCC增殖和迁移，并降低肿瘤相关巨噬细胞的M2极化。
空间分析全面表征了从正常组织到ESCC的分子和免疫特征，为更深入了解该疾病的肿瘤发生和进展提供了指导，并有助于ESCC的预防。在这项探索中，我们发现了与ESCC进展密切相关的生物标志物，为有洞察力的治疗方法提供了潜在的新途径。
