Neuroblastoma Invasion Strategies Are Regulated by the Extracellular Matrix
1
Cancer Bio-Engineering Group, Department of Anatomy and Regenerative Medicine, RCSI University of Medicine and Health Sciences, Dublin D02 YN77, Ireland
2
Cellular and Molecular Imaging Core, RCSI University of Medicine and Health Sciences, Dublin D02 YN77, Ireland
3
Center for Cell Dynamics, Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
4
Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79416, USA
5
Departments of Pediatrics and Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79416, USA
6
Departments of Chemical Engineering and Materials Science and Engineering, Faculty of Engineering, Monash University, Melbourne, VIC 3800, Australia
7
Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC 3800, Australia
8
Sidney Kimmel Comprehensive Cancer Center, Cancer Invasion and Metastasis Program, Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
9
School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin D02 YN77, Ireland
10
National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin D12 8MGH, Ireland
*
Author to whom correspondence should be addressed.
Academic Editors: Alice L. Yu and Shweta Joshi
Cancers 2021, 13(4), 736; https://doi.org/10.3390/cancers13040736
Received: 5 January 2021 / Revised: 30 January 2021 / Accepted: 4 February 2021 / Published: 10 February 2021
(This article belongs to the Special Issue The Tumor Microenvironment of Neuroblastoma)
Simple Summary
Paediatric cancer research in general and neuroblastoma, in particular, has minimal preclinical models of metastasis. As 50% of primary neuroblastomas have already metastasised at the time of diagnosis, it is important to develop models to understand the molecular mechanisms of neuroblastoma metastasis. Here, we describe a novel patient-derived xenograft (PDX)- and cell line-based organoid model. We found that the extracellular matrix (ECM) composition influenced the growth, viability and local invasion of organoids. PDX-derived neuroblastoma organoids displayed four various invasion phenotypes which were dependent on the local microenvironment, while cell lines were more restricted in their invasion strategies. These data support the use of organoid cultures for studying the biology and molecular basis of neuroblastoma invasion into normal tissues.
Neuroblastoma is a paediatric malignancy of the developing sympathetic nervous system. About half of the patients have metastatic disease at the time of diagnosis and a survival rate of less than 50%. Our understanding of the cellular processes promoting neuroblastoma metastases will be facilitated by the development of appropriate experimental models. In this study, we aimed to explore the invasion of neuroblastoma cells and organoids from patient-derived xenografts (PDXs) grown embedded in 3D extracellular matrix (ECM) hydrogels by time-lapse microscopy and quantitative image analysis. We found that the ECM composition influenced the growth, viability and local invasion of organoids. The ECM compositions induced distinct cell behaviours, with Matrigel being the preferred substratum for local organoid invasion. Organoid invasion was cell line- and PDX-dependent. We identified six distinct phenotypes in PDX-derived organoids. In contrast, NB cell lines were more phenotypically restricted in their invasion strategies, as organoids isolated from cell line-derived xenografts displayed a broader range of phenotypes compared to clonal cell line clusters. The addition of FBS and bFGF induced more aggressive cell behaviour and a broader range of phenotypes. In contrast, the repression of the prognostic neuroblastoma marker, MYCN, resulted in less aggressive cell behaviour. The combination of PDX organoids, real-time imaging and the novel 3D culture assays developed herein will enable rapid progress in elucidating the molecular mechanisms that control neuroblastoma invasion.
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Keywords:
neuroblastoma; organoids; 3D invasion assay; invasion phenotype; extracellular matrix environment (ECM)
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MDPI and ACS Style
Gavin, C.; Geerts, N.; Cavanagh, B.; Haynes, M.; Reynolds, C.P.; Loessner, D.; Ewald, A.J.; Piskareva, O. Neuroblastoma Invasion Strategies Are Regulated by the Extracellular Matrix. Cancers 2021, 13, 736. https://doi.org/10.3390/cancers13040736
AMA Style
Gavin C, Geerts N, Cavanagh B, Haynes M, Reynolds CP, Loessner D, Ewald AJ, Piskareva O. Neuroblastoma Invasion Strategies Are Regulated by the Extracellular Matrix. Cancers. 2021; 13(4):736. https://doi.org/10.3390/cancers13040736
Chicago/Turabian StyleGavin, Cian; Geerts, Nele; Cavanagh, Brenton; Haynes, Meagan; Reynolds, C. P.; Loessner, Daniela; Ewald, Andrew J.; Piskareva, Olga. 2021. "Neuroblastoma Invasion Strategies Are Regulated by the Extracellular Matrix" Cancers 13, no. 4: 736. https://doi.org/10.3390/cancers13040736
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