title: Genomic characterisation of small cell lung cancer patient-derived xenografts generated from endobronchial ultrasound-guided transbronchial needle aspiration specimens.
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.
authors.affiliation: MIMR-PHI Institute, Clayton, Victoria, Australia; Monash University, Clayton, Victoria, Australia.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Leong
authors.affiliation: MIMR-PHI Institute, Clayton, Victoria, Australia; Monash University, Clayton, Victoria, Australia.
authors.forename: Kieren D
authors.initials: KD
authors.lastname: Marini
authors.affiliation: Monash University, Clayton, Victoria, Australia; Life Sciences Computation Centre, Victorian Life Sciences Computation Initiative, Carlton, Victoria, Australia.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Rossello
authors.affiliation: MIMR-PHI Institute, Clayton, Victoria, Australia.
authors.forename: Samantha N
authors.initials: SN
authors.lastname: Jayasekara
authors.affiliation: Department of Anatomical Pathology, St Vincent's Hospital, Fitzroy, Melbourne, Victoria, Australia.
authors.forename: Prudence A
authors.initials: PA
authors.lastname: Russell
authors.affiliation: Department of Pathology, Monash Health, Clayton, Victoria, Australia.
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Prodanovic
authors.affiliation: Department of Pathology, Monash Health, Clayton, Victoria, Australia.
authors.forename: Beena
authors.initials: B
authors.lastname: Kumar
authors.affiliation: MIMR-PHI Institute, Clayton, Victoria, Australia; Monash University, Clayton, Victoria, Australia; Department of Medical Oncology, Monash Health, East Bentleigh, Victoria, Australia.
authors.forename: Vinod
authors.initials: V
authors.lastname: Ganju
authors.affiliation: MIMR-PHI Institute, Clayton, Victoria, Australia; Monash University, Clayton, Victoria, Australia; Department of Medical Oncology, Monash Health, East Bentleigh, Victoria, Australia.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Alamgeer
authors.affiliation: Department of Respiratory Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Louis B
authors.initials: LB
authors.lastname: Irving
authors.affiliation: Department of Respiratory Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Steinfort
authors.affiliation: Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Craig D
authors.initials: CD
authors.lastname: Peacock
authors.affiliation: MIMR-PHI Institute, Clayton, Victoria, Australia; Monash University, Clayton, Victoria, Australia.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Cain
authors.affiliation: MIMR-PHI Institute, Clayton, Victoria, Australia; Monash University, Clayton, Victoria, Australia.
authors.forename: Anette
authors.initials: A
authors.lastname: Szczepny
authors.affiliation: MIMR-PHI Institute, Clayton, Victoria, Australia; Monash University, Clayton, Victoria, Australia; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: D Neil
authors.initials: DN
authors.lastname: Watkins
mesh_terms: D000368:Aged; D000818:Animals; D001999:Bronchoscopy / Q000379:methods*; D061765:Endoscopic Ultrasound-Guided Fine Needle Aspiration / Q000379:methods*; D019160:Endosonography / Q000379:methods*; D005260:Female; D023281:Genomics / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D017422:Sequence Analysis, DNA / Q000379:methods; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured