2. Academic Validation
  3. Patient-derived organoids of pancreatic ductal adenocarcinoma for subtype determination and clinical outcome prediction

Patient-derived organoids of pancreatic ductal adenocarcinoma for subtype determination and clinical outcome prediction

  • J Gastroenterol. 2024 Apr 29. doi: 10.1007/s00535-024-02103-0.
Kazuhide Matsumoto 1,  Nao Fujimori # 2,  Kazuya Ichihara 3,  Ayumu Takeno 1,  Masatoshi Murakami 1,  Akihisa Ohno 1,  Shotaro Kakehashi 1,  Katsuhito Teramatsu 1,  Keijiro Ueda 1,  Kohei Nakata 4,  Osamu Sugahara 3,  Takeo Yamamoto 5,  Akinobu Matsumoto 3,  Keiichi I Nakayama 3,  Yoshinao Oda 5,  Masafumi Nakamura 4,  Yoshihiro Ogawa # 6
Affiliations

Affiliations

  • 1 Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
  • 2 Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. fujimori.nao.239@m.kyushu-u.ac.jp.
  • 3 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
  • 4 Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 5 Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 6 Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ogawa.yoshihiro.828@m.kyushu-u.ac.jp.
  • # Contributed equally.
PMID: 38684511 DOI: 10.1007/s00535-024-02103-0
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.

Keywords

Pancreatic ductal adenocarcinoma; Patient-derived organoids; Precision medicine; Subtype classification; Turnaround time.

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