A Comparative Study of Patient-Derived Tumor Models of Pancreatic Ductal Adenocarcinoma Involving Orthotopic Implantation

Kazuyoshi Yanagihara, Yuki Iino, Hiroshi Yokozaki, Takanori Kubo, Tatsuya Oda, Takashi Kubo, Masayuki Komatsu, Hiroki Sasaki, Hitoshi Ichikawa, Takeshi Kuwata, Toshio Seyama, Atsushi Ochiai

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Pancreatic ductal adenocarcinoma (PDA) is associated with very poor prognoses. Therefore, new therapies and preclinical models are urgently needed. In the present study, we sought to develop more realistic experimental models for use in PDA research. Methods: We developed patient-derived xenografts (PDXs), established PDX-derived cell lines (PDCLs), and generated cell line-derived xenografts (CDXs), which we integrated to create 13 matched "trios"- i.e., patient-derived tumor models of PDA. We then compared and contrasted histological and molecular alterations between these three model systems. Results: Orthotopic implantation (OI) of the PDCLs resulted in tumorigenesis and metastases to the liver and peritoneum. Morphological comparisons of OI-CDXs and OI-PDXs with passaged tumors revealed that the histopathological features of the original tumor were maintained in both models. Molecular alterations in PDX tumors (including those to KRAS, TP53, SMAD4, and CDKN2A) were similar to those in the respective PDCLs and CDX tumors. When gene expression levels in the PDCLs, ectopic tumors, and OI tumors were compared, the distant metastasis-promoting gene CXCR4 was specifically upregulated in OI tumors, whose immunohistochemical profiles suggested epithelial-mesenchymal transition and adeno-squamous trans-differentiation. Conclusion: These patient-derived tumor models provide useful tools for monitoring responses to antineoplastic agents and for studying PDA biology.

Original languageEnglish
JournalPathobiology
DOIs
Publication statusAccepted/In press - 2022

Keywords

  • Cell line-derived xenograft
  • Orthotopic implantation
  • Pancreatic ductal adenocarcinoma
  • Patient-derived xenograft
  • Preclinical model

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