Concerted epithelial and stromal changes during progression of Barrett's Esophagus to invasive adenocarcinoma exposed by multi-scale, multi-omics analysis

Esophageal adenocarcinoma arises from Barrett's esophagus, a precancerous metaplastic replacement of squamous by columnar epithelium in response to chronic inflammation. Multi-omics profiling, integrating single-cell transcriptomics, extracellular matrix proteomics, tissue-mechanics and spatial proteomics of the paths of progression from squamous epithelium through metaplasia, dysplasia to adenocarcinoma, in a total of 107 samples from 26 patients in two independent cohorts revealed shared and patient-specific progression characteristics. The metaplastic replacement of epithelial cells was paralleled by changes in stromal cells, ECM and tissue stiffness. Strikingly, this change in metaplasia was already accompanied by appearance of fibroblasts with characteristics of carcinoma-associated fibroblasts and of an NK cell-associated immunosuppressive microenvironment. Thus, Barrett's esophagus progresses as a coordinated multi-component system, supporting treatment paradigms that go beyond targeting cancerous cells to incorporate stromal reprogramming. Overall design: scRNAseq of normal, metaplastic, dysplastic and cancerous human esophageal tissue

食管腺癌（esophageal adenocarcinoma）起源于巴雷特食管（Barrett's esophagus）——一种因慢性炎症刺激，使食管鳞状上皮被柱状上皮替代的癌前化生病变。本研究针对从鳞状上皮经化生、异型增生至腺癌的疾病进展路径，整合了单细胞转录组学（single-cell transcriptomics）、细胞外基质蛋白质组学（extracellular matrix proteomics）、组织力学（tissue-mechanics）及空间蛋白质组学（spatial proteomics）数据，分析了来自两个独立队列、26名患者的共计107份样本，揭示了共有的及患者特异性的进展特征。上皮细胞的化生替代过程，同时伴随间质细胞、细胞外基质与组织硬度的改变。值得注意的是，在化生阶段便已出现具有癌相关成纤维细胞（carcinoma-associated fibroblasts）特征的成纤维细胞，以及与自然杀伤细胞（NK cell）相关的免疫抑制微环境。由此可见，巴雷特食管的进展是一个协同调控的多组分系统，这支持治疗范式应超越靶向癌细胞，纳入间质重编程策略的研究思路。整体实验设计：对正常、化生型、异型增生型及癌变型人食管组织开展单细胞RNA测序（scRNAseq）。