Genomic characterisation of small cell lung cancer patient-derived xenografts generated from endobronchial ultrasound-guided transbronchial needle aspiration specimens

PLoS One. 2014 Sep 5;9(9):e106862. doi: 10.1371/journal.pone.0106862. eCollection 2014.

Abstract

Patient-derived xenograft (PDX) models generated from surgical specimens are gaining popularity as preclinical models of cancer. However, establishment of PDX lines from small cell lung cancer (SCLC) patients is difficult due to very limited amount of available biopsy material. We asked whether SCLC cells obtained from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) could generate PDX lines that maintained the phenotypic and genetic characteristics of the primary tumor. Following successful EBUS-TBNA sampling for diagnostic purposes, we obtained an extra sample for cytologic analysis and implantation into the flanks of immunodeficient mice. Animals were monitored for engraftment for up to 6 months. Histopathologic and immunohistochemical analysis, and targeted next-generation re-sequencing, were then performed in both the primary sample and the derivative PDX line. A total of 12 patients were enrolled in the study. EBUS-TBNA aspirates yielded large numbers of viable tumor cells sufficient to inject between 18,750 and 1,487,000 cells per flank, and to yield microgram quantities of high-quality DNA. Of these, samples from 10 patients generated xenografts (engraftment rate 83%) with a mean latency of 104 days (range 63-188). All but one maintained a typical SCLC phenotype that closely matched the original sample. Identical mutations that are characteristic of SCLC were identified in both the primary sample and xenograft line. EBUS-TBNA has the potential to be a powerful tool in the development of new targeting strategies for SCLC patients by providing large numbers of viable tumor cells suitable for both xenografting and complex genomic analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Bronchoscopy / methods*
  • Endoscopic Ultrasound-Guided Fine Needle Aspiration / methods*
  • Endosonography / methods*
  • Female
  • Genomics / methods*
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology*
  • Male
  • Mice
  • Middle Aged
  • Neoplasm Transplantation
  • Sequence Analysis, DNA / methods
  • Small Cell Lung Carcinoma / genetics
  • Small Cell Lung Carcinoma / pathology*
  • Tumor Cells, Cultured

Associated data

  • SRA/SRP044662

Grant support

This work was supported by the Victorian Cancer Agency (www.victoriancanceragency.org.au), the National Health and Medical Research Council of Australia (www.nhmrc.gov.au), and the Victorian Government Operational Infrastructure Support Program (www.business.vic.gov.au/grants-and-assistance/programs/medical-research-operational-infrastructure-program). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.