Impact of extracellular matrix stiffness on genomic heterogeneity in MYCN-amplified neuroblastoma cell line

Journal of Experimental & Clinical Cancer Research

Beatriz Fernández-Blanco¹  Ezequiel Monferrer²  Amparo López-Carrasco²  Rebeca Burgos-Panadero²  Susana Martín-Vañó²  Rosa Noguera²  Samuel Navarro²  Ana P. Berbegall² 

[1] Department of Pathology, Medical School, University of Valencia/INCLIVA, Valencia, Spain;Department of Pathology, Medical School, University of Valencia/INCLIVA, Valencia, Spain;CIBERONC, Madrid, Spain;

关键词: Biotensegrity;    Clonal selection;    Stiffness;    Vitronectin;    Xenograft;    3D-bioprinting;   

DOI  :  10.1186/s13046-020-01729-1

来源: Springer

【 摘 要 】

BackgroundIncreased tissue stiffness is a common feature of malignant solid tumors, often associated with metastasis and poor patient outcomes. Vitronectin, as an extracellular matrix anchorage glycoprotein related to a stiff matrix, is present in a particularly increased quantity and specific distribution in high-risk neuroblastoma. Furthermore, as cells can sense and transform the proprieties of the extracellular matrix into chemical signals through mechanotransduction, genotypic changes related to stiffness are possible.MethodsWe applied high density SNPa and NGS techniques to in vivo and in vitro models (orthotropic xenograft vitronectin knock-out mice and 3D bioprinted hydrogels with different stiffness) using two representative neuroblastoma cell lines (the MYCN-amplified SK-N-BE(2) and the ALK-mutated SH-SY5Y), to discern how tumor genomics patterns and clonal heterogeneity of the two cell lines are affected.ResultsWe describe a remarkable subclonal selection of genomic aberrations in SK-N-BE(2) cells grown in knock-out vitronectin xenograft mice that also emerged when cultured for long times in stiff hydrogels. In particular, we detected an enlarged subclonal cell population with chromosome 9 aberrations in both models. Similar abnormalities were found in human high-risk neuroblastoma with MYCN amplification. The genomics of the SH-SY5Y cell line remained stable when cultured in both models.ConclusionsFocus on heterogeneous intratumor segmental chromosome aberrations and mutations, as a mirror image of tumor microenvironment, is a vital area of future research.

【 授权许可】

CC BY