The effect of extracellular matrix on the precision medicine utility of pancreatic cancer patient–derived organoids

• DOI: 10.1172/jci.insight.172419
• Publication Date: 2023-12-05T17:00:32Z
• Authors: Jan C. Lumibao; Shira R. Okhovat; Kristina L. Peck; Xiaoxue Lin; Kathryn Lande; Shira Yomtoubian; Isabella Ng; Hervé Tiriac; Andrew M. Lowy; Jingjing Zou; Dannielle D. Engle
• Keywords: Biomedical and clinical sciences; Biomedical and Clinical Sciences; Carcinoma; 610; Health sciences; Cell Biology; Extracellular matrix; Extracellular Matrix; Pancreatic Neoplasms; Organoids; Pancreatic Cancer; Mice; Rare Diseases; Good Health and Well Being; Oncology; Clinical Research; 5.1 Pharmaceuticals; Pancreatic Ductal; Humans; Animals; Drug therapy; Precision Medicine; Digestive Diseases; Cancer; Research Article

The use of patient-derived organoids (PDOs) to characterize therapeutic sensitivity and resistance is a promising precision medicine approach, and its potential to inform clinical decisions is now being tested in several large multi-institutional clinical trials. PDOs are cultivated in extracellular matrix from basement membrane extracts (BMEs) that are most commonly acquired commercially. Each clinical site utilizes distinct BME lots and may be restricted due to the availability of commercial BME sources. However, the impact of different sources of BMEs on organoid drug response is unknown. Here, we tested the impact of BME source on proliferation, drug response, and gene expression in mouse and human pancreatic ductal adenocarcinoma (PDA) organoids. Both human and mouse organoids displayed increased proliferation in Matrigel (Corning) compared to Cultrex (RnD) and UltiMatrix (RnD). However, we observed no substantial impact on drug response when organoids were cultured in Matrigel, Cultrex, or UltiMatrix. We also did not observe major shifts in gene expression across the different BME sources, and PDOs maintained their Classical or Basal-like designation. Overall, we find that BME source (Matrigel, Cultrex, UltiMatrix) does not shift PDO dose-response curves and drug testing results, indicating that PDO pharmacotyping is a robust approach for precision medicine.