title: Neuroblastoma patient-derived orthotopic xenografts retain metastatic patterns and geno- and phenotypes of patient tumours.
abstract: Neuroblastoma is a childhood tumour with heterogeneous characteristics and children with metastatic disease often have a poor outcome. Here we describe the establishment of neuroblastoma patient-derived xenografts (PDXs) by orthotopic implantation of viably cryopreserved or fresh tumour explants of patients with high risk neuroblastoma into immunodeficient mice. In vivo tumour growth was monitored by magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography. Neuroblastoma PDXs retained the undifferentiated histology and proliferative capacity of their corresponding patient tumours. The PDXs expressed neuroblastoma markers neural cell adhesion molecule, chromogranin A, synaptophysin and tyrosine hydroxylase. Whole genome genotyping array analyses demonstrated that PDXs retained patient-specific chromosomal aberrations such as MYCN amplification, deletion of 1p and gain of chromosome 17q. Thus, neuroblastoma PDXs recapitulate the hallmarks of high-risk neuroblastoma in patients. PDX-derived cells were cultured in serum-free medium where they formed free-floating neurospheres, expressed neuroblastoma gene markers MYCN, CHGA, TH, SYP and NPY, and retained tumour-initiating and metastatic capacity in vivo. PDXs showed much higher degree of infiltrative growth and distant metastasis as compared to neuroblastoma SK-N-BE(2)c cell line-derived orthotopic tumours. Importantly, the PDXs presented with bone marrow involvement, a clinical feature of aggressive neuroblastoma. Thus, neuroblastoma PDXs serve as clinically relevant models for studying and targeting high-risk metastatic neuroblastoma.
authors.affiliation: Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Noémie
authors.initials: N
authors.lastname: Braekeveldt
authors.forename: Caroline
authors.initials: C
authors.lastname: Wigerup
authors.forename: David
authors.initials: D
authors.lastname: Gisselsson
authors.forename: Sofie
authors.initials: S
authors.lastname: Mohlin
authors.forename: My
authors.initials: M
authors.lastname: Merselius
authors.forename: Siv
authors.initials: S
authors.lastname: Beckman
authors.forename: Tord
authors.initials: T
authors.lastname: Jonson
authors.forename: Anna
authors.initials: A
authors.lastname: Börjesson
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Backman
authors.forename: Irene
authors.initials: I
authors.lastname: Tadeo
authors.forename: Ana P
authors.initials: AP
authors.lastname: Berbegall
authors.forename: Ingrid
authors.initials: I
authors.lastname: Ora
authors.forename: Samuel
authors.initials: S
authors.lastname: Navarro
authors.forename: Rosa
authors.initials: R
authors.lastname: Noguera
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
authors.forename: Daniel
authors.initials: D
authors.lastname: Bexell
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019046:Bone Marrow Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D064593:Heterografts; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008297:Male; D051379:Mice; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger
keywords: MYCN; bone marrow metastasis; neuroblastoma; neuroblastoma metastasis; orthotopic xenograft; patient-derived xenograft