Establishment of a patient-derived intrahepatic cholangiocarcinoma xenograft model with KRAS mutation

Giuliana Cavalloni, Caterina Peraldo-Neia, Francesco Sassi, Giovanna Chiorino, Ivana Sarotto, Massimo Aglietta, Francesco Leone

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Intrahepatic cholangiocarcinoma (ICC) is an aggressive, highly lethal tumors and lacks of effective chemo and targeted therapies. Cell lines and animal models, even partially reflecting tumor characteristics, have limits to study ICC biology and drug response. In this work, we created and characterized a novel ICC patient-derived xenograft (PDX) model of Italian origin. Methods: Seventeen primary ICC tumors derived from Italian patients were implanted into NOD (Non-Obese Diabetic)/Shi-SCID (severe combined immunodeficient) mice. To verify if the original tumor characteristics were maintained in PDX, immunohistochemical (cytokeratin 7, 17, 19, and epithelial membrane antigen) molecular (gene and microRNA expression profiling) and genetic analyses (comparative genomic hybridization array, and mutational analysis of the kinase domain of EGFR coding sequence, from exons 18 to 21, exons 2 to 4 of K-RAS, exons 2 to 4 of N-RAS, exons 9 and 20 of PI3KCA, and exon 15 of B-RAF) were performed after tumor stabilization. Results: One out of 17 (5.8 %) tumors successfully engrafted in mice. A high molecular and genetic concordance between primary tumor (PR) and PDX was confirmed by the evaluation of biliary epithelial markers, tissue architecture, genetic aberrations (including K-RAS G12D mutation), and transcriptomic and microRNA profiles. Conclusions: For the first time, we established a new ICC PDX model which reflects the histology and genetic characteristics of the primary tumor, this model could represent a valuable tool to understand the tumor biology and the progression of ICC as well as to develop novel therapies for ICC patients.

Original languageEnglish
Article number90
JournalBMC Cancer
Volume16
Issue number1
DOIs
Publication statusPublished - Feb 11 2016

Keywords

  • Intrahepatic cholangiocarcinoma
  • K-RAS mutation
  • Patient derived xenograft

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

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