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- Title
Patient-derived organoids of pancreatic ductal adenocarcinoma for subtype determination and clinical outcome prediction.
- Authors
Matsumoto, Kazuhide; Fujimori, Nao; Ichihara, Kazuya; Takeno, Ayumu; Murakami, Masatoshi; Ohno, Akihisa; Kakehashi, Shotaro; Teramatsu, Katsuhito; Ueda, Keijiro; Nakata, Kohei; Sugahara, Osamu; Yamamoto, Takeo; Matsumoto, Akinobu; Nakayama, Keiichi I.; Oda, Yoshinao; Nakamura, Masafumi; Ogawa, Yoshihiro
- Abstract
Background: Recently, two molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) have been proposed: the "Classical" and "Basal-like" subtypes, with the former showing better clinical outcomes than the latter. However, the "molecular" classification has not been applied in real-world clinical practice. This study aimed to establish patient-derived organoids (PDOs) for PDAC and evaluate their application in subtype classification and clinical outcome prediction. Methods: We utilized tumor samples acquired through endoscopic ultrasound-guided fine-needle biopsy and established a PDO library for subsequent use in morphological assessments, RNA-seq analyses, and in vitro drug response assays. We also conducted a prospective clinical study to evaluate whether analysis using PDOs can predict treatment response and prognosis. Results: PDOs of PDAC were established at a high efficiency (> 70%) with at least 100,000 live cells. Morphologically, PDOs were classified as gland-like structures (GL type) and densely proliferating inside (DP type) less than 2 weeks after tissue sampling. RNA-seq analysis revealed that the "morphological" subtype (GL vs. DP) corresponded to the "molecular" subtype ("Classical" vs. "Basal-like"). The "morphological" classification predicted the clinical treatment response and prognosis; the median overall survival of patients with GL type was significantly longer than that with DP type (P < 0.005). The GL type showed a better response to gemcitabine than the DP type in vitro, whereas the drug response of the DP type was improved by the combination of ERK inhibitor and chloroquine. Conclusions: PDAC PDOs help in subtype determination and clinical outcome prediction, thereby facilitating the bench-to-bedside precision medicine for PDAC.
- Subjects
TREATMENT effectiveness; PANCREATIC duct; ORGANOIDS; ADENOCARCINOMA; OVERALL survival; PANCREATIC intraepithelial neoplasia
- Publication
Journal of Gastroenterology, 2024, Vol 59, Issue 7, p629
- ISSN
0944-1174
- Publication type
Article
- DOI
10.1007/s00535-024-02103-0