Tumor-intrinsic signatures of esophageal adenocarcinoma associate with cellular phenotypes and responses to therapy [snRNA-Seq]

However, identifying a mesenchymal molecular subtype at the tissue level has been hampered by the abundance of non-tumor cells in EAC. Here, we apply non-negative matrix factorization on gene expression data of 186 esophageal cancer samples to separate cellular compartments and identify tumor-specific features.

Tumor-intrinsic gene expression, together with single-nucleus RNA sequencing, reveals the existence of two distinct signatures defining subtypes of EAC; intestinal-like and mesenchymal-like. The mesenchymal-like subtype enriches following neoadjuvant chemoradiation and during disease progression, and predicts poor treatment response. Silencing of transcriptional regulators reverses the mesenchymal phenotype and reduces invasiveness.