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

Autores de INCLIVA

• 

  María Amparo López Carrasco

  Autor

• 

  Susana Martín Vañó

  Autor

• Rebeca Burgos Panadero

  Autor

• 

  Ezequiel Monferrer Garzarán

  Autor

• Ana Pilar Berbegall Beltrán

  Autor

• Beatriz Fernandez Blanco

  Autor

• 

  Samuel Navarro Fos

  Autor

• 

  Rosa Noguera Salva

  Autor

Grupos y Plataformas de I+D+i

• Grupo de Investigación Translacional de Tumores Sólidos Pediátricos

  

  Leading Researcher

  Samuel Navarro Fos

Abstract

BACKGROUND: Increased 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: Focus on heterogeneous intratumor segmental chromosome aberrations and mutations, as a mirror image of tumor microenvironment, is a vital area of future research.

© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data mad

Keywords

• Biotensegrity; Clonal selection; Stiffness; Vitronectin; Xenograft; 3D-bioprinting