P1.105. Epithelial–Mesenchymal Plasticity Underlies Adaptive Resistance to FLOT Chemotherapy in Esophageal Adenocarcinoma
TL;DR
Findings suggest a dynamic, reversible model of chemoresistance driven by EMP rather than fixed cell identity, which may support the development of treatment strategies that limit resistance and improve patient response to perioperative chemotherapy.
Abstract
Esophageal Cancer: Molecular Biology/Pathology Resistance to perioperative FLOT chemotherapy remains a major determinant of poor outcome in esophageal adenocarcinoma. Epithelial–mesenchymal plasticity (EMP) enables dynamic cell state transitions that may promote adaptive chemoresistance, yet its functional contribution to chemoresistance in esophageal adenocarcinoma remains insufficiently characterized. Esophageal adenocarcinoma cell models were engineered to stably express a dual-fluorescent reporter system driven by E-cadherin and vimentin promoters, allowing real-time visualization of epithelial, mesenchymal, and hybrid epithelial/mesenchymal (E/M) states. Fluorescence-Activated Cell Sorting was used to isolate phenotypically distinct subpopulations. Sensitivity to FLOT chemotherapy was assessed using cell viability and clonogenic survival. Dynamic state transitions were evaluated following chemotherapy exposure. RNA sequencing on sorted populations will enable the identification of transcriptional programs associated with chemoresistance and EMP. Distinct epithelial–mesenchymal subpopulations were identified across several cellular models, with marked heterogeneity. One model, FLO1, exhibited all three phenotypic states, including a hybrid E/M population indicative of high plasticity. FLOT chemotherapy exposure induced significant phenotypic shifts toward hybrid states, accompanied by increased survival and persistence of this cell subset. These findings suggest a dynamic, reversible model of chemoresistance driven by EMP rather than fixed cell identity. Epithelial–mesenchymal plasticity promotes adaptive resistance to FLOT chemotherapy in esophageal adenocarcinoma by enabling dynamic transitions toward therapy-tolerant states. Defining molecular programs underlying these transitions may support the development of treatment strategies that limit resistance and improve patient response to perioperative chemotherapy.