Concerted epithelial and stromal changes during progression of Barret'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 64 samples from 12 patients' paths of progression from squamous epithelium through metaplasia, dysplasia to adenocarcinoma, revealed shared and patient-specific progression characteristics. The classic metaplastic replacement of epithelial cells was paralleled by metaplastic changes in stromal cells, ECM and tissue stiffness. Strikingly, this change in tissue state at 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 incorporating stromal reprogramming. Overall design: We performed single cell RNA sequencing (scRNA-seq) on adjacent normal (gastritis), metaplastic, dysplastic, or cancerous stomach tissues from 5 patients with gastric cancer.

食管腺癌起源于巴雷特食管（Barrett's esophagus），这是一种癌前病变：在慢性炎症刺激下，食管鳞状上皮被柱状上皮替代的化生性改变。本研究对12例患者从鳞状上皮经化生、异型增生进展至腺癌的病程中获取的64份样本开展多组学表征分析，整合了单细胞转录组学、细胞外基质（extracellular matrix, ECM）蛋白质组学、组织力学检测与空间蛋白质组学，由此揭示了共有的以及患者特异性的进展特征。经典的上皮细胞化生替代过程，同步伴随基质细胞、细胞外基质及组织硬度的化生改变。令人意外的是，在化生阶段的组织状态改变中，就已出现携带癌相关成纤维细胞（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。综上，巴雷特食管的进展是一个协同调控的多组分系统，这支持了全新的治疗范式：不再仅靶向癌细胞，而是需纳入基质细胞重编程策略。实验设计概述：我们对5例胃癌患者的相邻正常（胃炎）组织、化生组织、异型增生组织及癌变胃部组织开展了单细胞RNA测序（scRNA-seq）。