Tumor-intrinsic signatures of esophageal adenocarcinoma associate with cellular phenotypes and responses to therapy

ABSTRACT: Treatment of esophageal adenocarcinoma (EAC) is challenging, among others due to high mesenchymal plasticity, leading to therapy resistance and disease recurrence. Identifying a mesenchymal molecular subtype at the tissue-level for patient stratification has posed challenges due to non-tumor cells interfering with gene expression data. Here, we conducted gene expression profiling from 186 esophageal cancer samples and applied non-negative matrix factorization (NMF) to segregate tumor cellular compartments and identify tumor-intrinsic features. Tumor-intrinsic gene expression, together with single-nucleus RNA sequencing analysis, revealed the existence of two distinct signatures defining subtypes; intestinal-like and mesenchymal-like. The latter was enriched after neoadjuvant chemoradiation treatment and during disease progression. In a separate cohort of RNA-sequenced metastatic EAC, the mesenchymal-like subtype was found to predict poor response to treatment. Conversely, intestinal-like subtype cancer cells had highly active epidermal growth factor signaling determined by phosphoproteomics, and were sensitive to receptor tyrosine kinase inhibition. Regulators of the mesenchymal-like subtype were identified and silencing of these transcription factors reverted the mesenchymal phenotype and invasiveness. In conclusion, we describe two previously unrecognized molecular subtypes in EAC that feature distinct tumor biology and clinical outcomes, and identified their regulatory mechanisms and therapeutic vulnerabilities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254660 | GEO | 2026/08/26

REPOSITORIES: GEO