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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.

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