Patient-Derived Organoids from Multiple Sites of a Single Tumor Recapitulates Intratumoral Heterogeneity in Patients with Gastric Cancer

Abstract

Background/Aims: Patient-derived organoids (PDOs) are promising preclinical models that replicate critical tumor features. However, intratumoral heterogeneity challenges the clinical utility of PDOs, especially in capturing diverse tumor cell subpopulations. Methods: Single-cell transcriptomics was used to analyze PDOs from distinct sites within a single gastric cancer tumor, aiming to assess their ability to reflect intratumoral heterogeneity. Results: The PDOs displayed similarities in gene expression but also exhibited distinct profiles. Single-cell analysis of PDOs revealed upregulation of markers for neuroendocrine tumors, which was validated via immunohistochemistry staining of neuron-specific enolase in the primary tumor. Notably, heat shock proteins showed significant variability among the PDOs, impacting immune responses. Tumors with abundant heat shock proteins are reported to have increased cytotoxic T cell activity. Conclusions: Intratumoral heterogeneity poses challenges for PDO-based models, highlighting the need for comprehensive assessment. Despite their limitations, PDOs offer valuable insights into precision medicine for patients with gastric cancer, aiding in the development of therapeutic strategies. (Gut Liver, Published online September 5, 2025)