Gastric adenocarcinoma (GAC) remains a leading cause of cancer-related mortality, particularly in patients with peritoneal carcinomatosis, for whom effective therapies are limited. We investigated the therapeutic efficacy and molecular mechanism of CYD-4-61, a BAX activator, using human GAC cell lines, patient-derived xenograft models, genetically engineered mouse models, and a syngeneic mouse model. CYD-4-61 potently inhibited tumor cell proliferation, induced apoptosis, and suppressed cancer stem cell-like properties, with enhanced activity in radiation-resistant GAC cells. Mechanistically, CYD-4-61 activated the BAX-caspase pathway, leading to SOX9 protein reduction. Integrated bulk and single-cell transcriptomic analyses identified SOX9-dependent transcriptional programs as major targets of CYD-4-61. Functional rescue experiments together with chromatin immunoprecipitation and CUT&RUN analyses supported CDK4 as a SOX9-regulated gene and demonstrated suppression of the SOX9-CDK4 regulatory axis following CYD-4-61 treatment. In multiple preclinical models, CYD-4-61 significantly inhibited tumor growth and improved the therapeutic response to anti-programmed cell death protein 1 (PD-1) therapy while modulating the tumor immune microenvironment. Clinically, co-expression of SOX9 and CDK4 was associated with diffuse-type GAC and poor patient outcomes. These findings identify the BAX-SOX9-CDK4 axis as an important mechanism contributing to the antitumor activity of CYD-4-61 and provide a strong preclinical rationale for its further development as a therapeutic strategy for aggressive GAC.
Gengyi Zou, Katsuhiro Yoshimura, Yibo Fan et al.· Cancer Letters· 0 citations
Esophageal adenocarcinoma (EAC) is a highly lethal malignancy with rising incidence and poor survival, and is increasingly recognized as a rare but aggressive cancer subtype with limited therapeutic options. Barrett’s esophagus (BE), the only known precursor, progresses through low-grade dysplasia (LGD) and high-grade dysplasia (HGD) to invasive cancer; however, the molecular mechanisms driving this transition remain poorly understood. While genomic alterations have been cataloged, they do not fully explain the dynamic and heterogeneous progression observed in patients. Emerging evidence suggests that epigenetic plasticity is a central driver of this process, particularly in rare cancers where non-genetic mechanisms contribute disproportionately to disease evolution. In this study, we define the role of epigenetic reprogramming in BE-to-EAC progression by integrating spatial transcriptomics, single-cell analyses, and functional modeling. Using high-resolution CosMx spatial molecular imaging, we profiled BE, LGD, HGD, and EAC tissues to map spatially resolved epithelial and microenvironmental cell states. Our data reveal a progressive increase in transcriptional heterogeneity and enhancer-associated gene expression programs across disease stages, accompanied by early DNA methylation changes and widespread chromatin remodeling. Spatial analyses identify distinct epithelial niches characterized by activation of oncogenic signaling pathways, including receptor tyrosine kinase and MYC-driven programs, as well as secretory and inflammatory phenotypes. These epigenetically defined tumor states are tightly coupled to specific stromal and immune microenvironments, suggesting that niche interactions reinforce and stabilize malignant cell states. Integration of single-cell and spatial datasets demonstrates that enhancer activation correlates with transitions from stable epithelial identity to highly plastic, dysplastic, and malignant phenotypes. Functional studies in organoid and in vitro models further support a model in which chronic injury and inflammation drive epigenetic remodeling, leading to enhancer reprogramming and sustained oncogenic transcriptional activation. This epigenetically driven plasticity promotes tumor evolution, cellular heterogeneity, and progression to invasive cancer. Collectively, our findings position epigenetic plasticity as a fundamental mechanism underlying malignant progression in this rare cancer context. By linking enhancer activation to spatially organized tumor states and microenvironmental interactions, this work provides a conceptual and translational framework for identifying actionable epigenetic vulnerabilities. These insights have the potential to inform early detection strategies and enable precision therapeutic interventions to intercept progression in BE and improve outcomes for patients with EAC.
Shilpa S. Dhar, Jaffer S. Ajani. Genomic and epigenomic complexity underlies barrett’s esophagus progression to adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr B039.
Shilpa S. Dhar, Jaffer S. Ajani· Cancer Research· 0 citations
