268. DEVELOPMENT OF A NOVEL ESOPHAGUS-ON-A-CHIP MODEL: A HIGH-FIDELITY PLATFORM FOR DIRECTING PERSONALIZED THERAPY IN ESOPHAGEAL ADENOCARCINOMA
Sanjima Pal, Elee Shimshoni, Salvador Flores-Torres, Julie Bérubé, Mingyang Kong, Betty Giannias, Sean Hall, Nicholas Bertos, Veena Sangwan, Donald Ingber, Lorenzo Ferri- Gastroenterology
- General Medicine
Abstract
Background
80% of patients diagnosed with esophageal adenocarcinoma (EAC) die of disease. Current standard of care for EAC is systemic cytotoxic, platinum-based neoadjuvant chemotherapy followed by resection and additional rounds of chemotherapy. Locally advanced, resectable patients often fail to respond due to intrinsic and/or acquired chemoresistance. Traditional preclinical models fail to offer alternative salvage options. To our knowledge, this is the first high-fidelity dynamic 3D platform implemented to study esophageal function, pathophysiology, and drug effects.
Methods
Primary tissues obtained from EAC patients at diagnostic biopsy were propagated into patient-derived organoids (PDOs). The upper (mucosal) channel of the esophagus-chip was designated for PDO-derived epithelial cells, while the lower stromal channel was designated for matched fibroblasts. Autologous cell types were exposed to a physiologically relevant flow of nutrient media and microtissues were formed. Epithelial permeability was determined by cascade blue assay. Using this model, a clinically relevant chemotherapy protocol was administered to study patient-specific tumor response. To determine microtissue development and cellular fate in response to chemotherapy, level of several epithelial/mesenchymal biomarkers were evaluated.
Results
Study cohort consisted of both chemo-sensitive and -resistant EAC patients. Esophagus-chip models were developed with samples from patient-matched tumor and normal tissue. Chips recapitulated morphological and histological features of their parental tissues. Epithelial barrier integrity was established within 5 days on-chip. Scanning electron microscopy revealed the presence of pleomorphic cells and mature microvilli in EAC-chips. In vitro administration of docetaxel triplet chemotherapy demonstrated efficacy similar to that observed in the clinical setting when assessed directly or indirectly. Confocal imaging revealed treatment-associated differential expression of epithelial (CK7, CK19), and mesenchymal (vimentin) markers.
Conclusion
3D-organoids conserve cellular heterogeneity of source patients, whereas esophagus-on-chip expand on this diversity by adding microphysiological relevance, stromal influence & flexible complexity. This high-fidelity biomimetic platform enables clinical mimicry and can predict patient-specific chemosensitivity within a clinically relevant timeframe. This esophagus-chip system is a promising potential replacement for both inefficient preclinical animal models and existing tumor-only avatars lacking stromal and microphysiological context.