Abstract 1361: KDM2A-driven epigenetic reprogramming promotes barrett’s esophagus progression to adenocarcinoma.

Abstract Purpose: Esophageal adenocarcinoma (EAC), a rapidly increasing and highly lethal cancer arising from Barrett’s esophagus (BE), lacks effective preventive strategies. Our study investigates the histone demethylase KDM2A as an early epigenetic driver of BE-to-EAC progression and evaluates whether its inhibition can suppress oncogenic reprogramming and tumorigenesis. Experimental Procedures: We performed high-plex spatial transcriptomics (COSMx, 1K human panel) on patient tissues spanning BE, low- and high-grade dysplasia, and EAC (n = 20), integrating these results with immunohistochemistry, immunofluorescence, and TCGA (n = 186) datasets. Functional studies employed patient-derived organoids (PDOs), xenografts, and CRISPR-based KDM2A perturbation models. Chromatin profiling (CUT&RUN for KDM2A, ATAC-seq, RNA-seq) was used to map KDM2A-dependent enhancer activation and tumor suppressor repression. Results: Spatial transcriptomics identified 13 transcriptional clusters delineating epithelial, stromal, and immune compartments. Progression from BE to EAC was characterized by expansion of stem-like epithelial clusters and loss of differentiation markers. PSCA and SPINK1 were consistently upregulated in EAC and correlated with increased EGFR expression, suggesting a convergence of these pathways in promoting therapy resistance and malignancy. KDM2A expression, validated by IHC/IF, was elevated in 4/6 EAC versus 1/3 BE samples and strongly correlated with PSCA and SPINK1. Analysis of TCGA-EAC confirmed KDM2A amplification and overexpression, which correlated with ERBB2, MYC, EGFR, and poor overall survival (p=8.67×10-3). Downstream analysis revealed repression of tumor suppressors DMBT1 and PFN1, implicating KDM2A in chromatin remodeling that silences protective loci while activating oncogenic enhancers. In organoid models, genetic or pharmacologic inhibition of KDM2A reduced PSCA/SPINK1 and EGFR signaling, restored differentiation, and suppressed proliferation. Conclusions: KDM2A acts as a master chromatin regulator linking histone demethylation, tumor suppressor silencing, and activation of the PSCA-SPINK1-EGFR oncogenic axis during BE-to-EAC progression. Co-targeting KDM2A with EGFR/HER2 or MYC/CDK9 inhibitors represents a rational therapeutic strategy for early intervention and prevention. This study provides mechanistic insight into how epigenetic deregulation establishes a stem-like, therapy-resistant state in EAC and identifies KDM2A as a promising preventive and therapeutic target. Citation Format: Shilpa S. Dhar, Johnson Amoah, Ferhad Mongal, Liyong Zeng, Aryana S. Bhati, Xueshuai Han, Fang Cao, Tanaya Alexander Washington, MelissaPizzi Pizzi, Bansi Vanparia, Calena J. Brown, Gengyi Zou, Min Gyu Lee, Linghua Wang, Jaffer A. Ajani. KDM2A-driven epigenetic reprogramming promotes barrett’s esophagus progression to adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1361.