Identifying the origin of cancer
Many cancers are classified on the basis of the organ or tissue from which they originated. However, identifying the specific cells and conditions that precede tumorigenesis can help us understand and better treat the resulting disease. Nowicki-Osuch et al. used a single-cell approach to investigate the cell of origin for Barrett’s esophagus (BE) and the mechanisms leading to the development of esophageal adenocarcinoma (EAC) (see the Perspective by Geboes and Hoorens). Analyses of healthy human esophageal tissues, mutational lineage tracing, and organoid models revealed that BE originates from the gastric cardia and that EAC arises from undifferentiated BE cells. This analysis provides a map of the transcriptional landscape of the healthy esophagus that can be compared with mouse models of disease.
Science, abd1449, this issue p. 760; see also abj9797, p. 737
Abstract
The origin of human metaplastic states and their propensity for cancer is poorly understood. Barrett’s esophagus is a common metaplastic condition that increases the risk for esophageal adenocarcinoma, and its cellular origin is enigmatic. To address this, we harvested tissues spanning the gastroesophageal junction from healthy and diseased donors, including isolation of esophageal submucosal glands. A combination of single-cell transcriptomic profiling, in silico lineage tracing from methylation, open chromatin and somatic mutation analyses, and functional studies in organoid models showed that Barrett’s esophagus originates from gastric cardia through c-MYC and HNF4A-driven transcriptional programs. Furthermore, our data indicate that esophageal adenocarcinoma likely arises from undifferentiated Barrett’s esophagus cell types even in the absence of a pathologically identifiable metaplastic precursor, illuminating early detection strategies.