Biliary tract cancer patient-derived xenografts: Surgeon impact on individualized medicine

Jennifer L. Leiting, Stephen J. Murphy, John R. Bergquist, Matthew C. Hernandez, Tommy Ivanics, Amro M. Abdelrahman, Lin Yang, Isaac Lynch, James Smadbeck, Sean P. Cleary, David M. Nagorney, Michael S. Torbenson, Rondell P. Graham, Lewis R. Roberts, Gregory J. Gores, Rory Smoot, Mark Truty

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Background & Aims: Biliary tract tumors are uncommon but highly aggressive malignancies with poor survival outcomes. Due to their low incidence, research into effective therapeutics has been limited. Novel research platforms for pre-clinical studies are desperately needed. We sought to develop a patient-derived biliary tract cancer xenograft catalog. Methods: With appropriate consent and approval, surplus malignant tissues were obtained from surgical resection or radiographic biopsy and implanted into immunocompromised mice. Mice were monitored for xenograft growth. Established xenografts were verified by a hepatobiliary pathologist. Xenograft characteristics were correlated with original patient/tumor characteristics and oncologic outcomes. A subset of xenografts were then genomically characterized using Mate Pair sequencing (MPseq). Results: Between October 2013 and January 2018, 87 patients with histologically confirmed biliary tract carcinomas were enrolled. Of the 87 patients, 47 validated PDX models were successfully generated. The majority of the PDX models were created from surgical resection specimens (n = 44, 94%), which were more likely to successfully engraft when compared to radiologic biopsies (p = 0.03). Histologic recapitulation of original patient tumor morphology was observed in all xenografts. Successful engraftment was an independent predictor for worse recurrence-free survival. MPseq showed genetically diverse tumors with frequent alterations of CDKN2A, SMAD4, NRG1, TP53. Sequencing also identified worse survival in patients with tumors containing tetraploid genomes. Conclusions: This is the largest series of biliary tract cancer xenografts reported to date. Histologic and genomic analysis of patient-derived xenografts demonstrates accurate recapitulation of original tumor morphology with direct correlations to patient outcomes. Successful development of biliary cancer tumografts is feasible and may be used to direct subsequent therapy in high recurrence risk patients. Lay summary: Patient biliary tract tumors grown in immunocompromised mice are an invaluable resource in the treatment of biliary tract cancers. They can be used to guide individualized cancer treatment in high-risk patients.

Original languageEnglish (US)
Article number100068
JournalJHEP Reports
Volume2
Issue number2
DOIs
StatePublished - Apr 2020

Keywords

  • biliary tract
  • cholangiocarcinoma
  • gallbladder carcinoma
  • MatePair sequencing
  • Patient-derived xenografts

ASJC Scopus subject areas

  • Immunology and Allergy
  • Internal Medicine
  • Hepatology
  • Gastroenterology

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