Neuroblastoma patient‐derived orthotopic xenografts retain metastatic patterns and geno‐ and phenotypes of patient tumours

• Published in: International journal of cancer Vol. 136; no. 5; pp. E252 - E261
• Main Authors: Braekeveldt, Noémie, Wigerup, Caroline, Gisselsson, David, Mohlin, Sofie, Merselius, My, Beckman, Siv, Jonson, Tord, Börjesson, Anna, Backman, Torbjörn, Tadeo, Irene, Berbegall, Ana P., Öra, Ingrid, Navarro, Samuel, Noguera, Rosa, Påhlman, Sven, Bexell, Daniel
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2015; Wiley Periodicals, Inc
• Subjects: Animals; Blotting, Western; Bone marrow; bone marrow metastasis; Bone Marrow Neoplasms - genetics; Bone Marrow Neoplasms - metabolism; Bone Marrow Neoplasms - secondary; Cancer; Cancer and Oncology; Cancer Cell Biology; Cancer och onkologi; Cell adhesion & migration; Child; Child, Preschool; Clinical Medicine; Female; Genotype; Heterografts; Humans; Immunoenzyme Techniques; Infant; Klinisk medicin; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Male; Medical and Health Sciences; Medical research; Medicin och hälsovetenskap; Metastasis; Mice; MYCN; neuroblastoma; Neuroblastoma - genetics; Neuroblastoma - metabolism; Neuroblastoma - pathology; neuroblastoma metastasis; orthotopic xenograft; Patients; patient‐derived xenograft; Phenotype; Polymorphism, Single Nucleotide - genetics; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Tumor Cells, Cultured; Tumors; neuroblastoma; orthotopic xenograft; MYCN; bone marrow metastasis; patient-derived xenograft; neuroblastoma metastasis
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29217

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. What's new? Neuroblastoma is a childhood tumour with heterogeneous characteristics and children with metastatic disease have a poor outcome. Here, the authors established neuroblastoma patient‐derived xenografts (PDXs) by orthotopic implantation of viably cryopreserved or fresh tumour explants of patients with high‐risk neuroblastoma into immunodeficient mice. The PDXs retained the genotype and phenotype of patient tumours and exhibited substantial infiltrative growth and metastasis to distant organs including bone marrow. PDX‐derived neuroblastoma cells were expanded in vitro and retained tumourigenic and metastatic capacity in vivo. The PDXs may thus represent an important tool for investigating neuroblastoma growth and metastasis as well as drug targeting.