Molecular phenotyping reveals the identity of Barrett’s esophagus and its malignant transition

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.

A spatial multi-omics atlas of the human lung reveals a novel immune cell survival niche

“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in Identification of duct and myoepithelial cells of the human airway submucosal glands (SMG) Further analysis of the epithelial compartment (excluding AT1 and AT2 cells) identified expected ciliated, goblet, basal, suprabasal, dividing basal, club, SMG mucous and serous populations along with rare deuterosomal, ionocyte & brush and neuroendocrine cells. In addition to these, we identified a novel population between serous, mucous and club/goblet cells (Figure 4a, Figure S8 a, b) with marker genes overlapping with SMG duct cells in human oesophagus and preferential localisation in trachea (Madissoon et al 2019;Nowicki-Osuch et al 2021). Thus, we hypothesise that these cells are the columnar non-ciliated duct cells of the human airway, previously only characterised in mice at the single cell level (Widdicombe and Wine 2015;Meyrick, Sturgess, and Reid 1969;A.…”

Barrett's esophagus stages: their correlation with SBS17-associated DNA mutations and the identification of histological marker genes

“…Single-cell RNA-sequencing (scRNAseq) is an attractive approach to identify such marker genes. While others focused their analyses on NDBE biopsies 2 or did not specify the respective BE stages, 3 we performed scRNAseq experiments with biopsies corresponding to different BE stages. 4 Our analysis identified two sets of marker genes that distinguish between BE with and without IM, and CLDN2 as a marker gene for dysplastic BE stages.…”

Challenges in Determining the Role of Microbiome Evolution in Barrett’s Esophagus and Progression to Esophageal Adenocarcinoma

“…The only established precursor to EAC is BE [7], and successive histological stages of low-grade dysplasia (LGD) and high-grade dysplasia (HGD) increase the risk of developing EAC within premalignant BE. Underlying BE is likely responsible for all EAC [4,5]; this implies that to prevent EAC and understand its early stages of progression, we need to first better understand the neoplastic transformation of BE.…”

“…The alarming increase in EAC cases, along with its continued poor prognosis, despite diagnostic and therapeutic advances in this space, signals a knowledge gap in our understanding of EAC pathogenesis and risk of progression to EAC from preneoplastic tissue (i.e., Barrett's esophagus). Although nearly all EAC tumors are expected to arise in Barrett's esophagus (BE) [4,5], only a small minority of EAC cases are diagnosed in patients actively enrolled in BE surveillance programs designed to catch cancers earlier [6]. Consequently, current BE surveillance strategies do not benefit most patients who eventually progress to EAC, and improvements in both early detection and effective monitoring are needed to provide this benefit.…”