Concerted changes in Epithelium and Stroma: a multi-scale, multi-omics analysis of progression from Barrett's...

Esophageal adenocarcinoma arises from Barrett's esophagus, a metaplastic condition. 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 107 samples from 26 patients in two independent cohorts, defined shared and patient-specific progression characteristics. Metaplastic replacement of epithelial cell composition and architecture was paralleled by changes in stromal cells, extracellular matrix (ECM) and tissue stiffness. This change in pre-cancerous metaplasia was already accompanied by appearance of fibroblasts with the molecular characteristics of carcinoma-associated fibroblasts. These fibroblasts produced the immunosuppressive protein POSTN, whose expression shifted from vascular to stromal cells, consistent with the emergence of an immunosuppressive microenvironment evident in cell neighborhoods enriched for immunoregulatory NK and Treg cells. Thus, Barrett's esophagus progresses as a coordinated multi-component system, supporting treatment paradigms that go beyond targeting cancerous cells to incorporate stromal reprogramming.