title: Neuroblastoma patient-derived orthotopic xenografts reflect the microenvironmental hallmarks of aggressive patient tumours.
abstract: Treatment of high-risk childhood neuroblastoma is a clinical challenge which has been hampered by a lack of reliable neuroblastoma mouse models for preclinical drug testing. We have previously established invasive and metastasising patient-derived orthotopic xenografts (PDXs) from high-risk neuroblastomas that retained the genotypes and phenotypes of patient tumours. Given the important role of the tumour microenvironment in tumour progression, metastasis, and treatment responses, here we analysed the tumour microenvironment of five neuroblastoma PDXs in detail. The PDXs resembled their parent tumours and retained important stromal hallmarks of aggressive lesions including rich blood and lymphatic vascularisation, pericyte coverage, high numbers of cancer-associated fibroblasts, tumour-associated macrophages, and extracellular matrix components. Patient-derived tumour endothelial cells occasionally formed blood vessels in PDXs; however, tumour stroma was, overall, of murine origin. Lymphoid cells and lymphatic endothelial cells were found in athymic nude mice but not in NSG mice; thus, the choice of mouse strain dictates tumour microenvironmental components. The murine tumour microenvironment of orthotopic neuroblastoma PDXs reflects important hallmarks of aggressive and metastatic clinical neuroblastomas. Neuroblastoma PDXs are clinically relevant models for preclinical drug testing.
authors.affiliation: Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Noémie
authors.initials: N
authors.lastname: Braekeveldt
authors.affiliation: Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Wigerup
authors.affiliation: Department of Pathology, Medical School, University of Valencia-INCLIVA, Valencia, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Tadeo
authors.affiliation: Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Siv
authors.initials: S
authors.lastname: Beckman
authors.affiliation: Department of Experimental Medical Science, Lund University and Medetect AB, Lund, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sandén
authors.affiliation: Department of Experimental Medical Science, Lund University and Medetect AB, Lund, Sweden.
authors.forename: Jimmie
authors.initials: J
authors.lastname: Jönsson
authors.affiliation: Department of Experimental Medical Science, Lund University and Medetect AB, Lund, Sweden.
authors.forename: Jonas S
authors.initials: JS
authors.lastname: Erjefält
authors.affiliation: Department of Pathology, Medical School, University of Valencia-INCLIVA, Valencia, Spain.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Berbegall
authors.affiliation: Department of Paediatric Surgery, Skåne University Hospital, Lund, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Börjesson
authors.affiliation: Department of Paediatric Surgery, Skåne University Hospital, Lund, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Backman
authors.affiliation: Department of Paediatrics, Paediatric Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Øra
authors.affiliation: Department of Pathology, Medical School, University of Valencia-INCLIVA, Valencia, Spain.
authors.forename: Samuel
authors.initials: S
authors.lastname: Navarro
authors.affiliation: Department of Pathology, Medical School, University of Valencia-INCLIVA, Valencia, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Noguera
authors.affiliation: Department of Clinical Genetics, Lund University, Lund, Sweden; Department of Pathology, University and Regional Laboratories, Lund, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Gisselsson
authors.affiliation: Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
authors.affiliation: Translational Cancer Research, Lund University, Lund, Sweden. Electronic address: daniel.bexell@med.lu.se.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bexell
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000473:pathology*; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D059016:Tumor Microenvironment / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
keywords: Metastasis; Neuroblastoma; Paediatric cancer; Patient-derived xenograft (PDX); Tumour microenvironment; Tumour stroma