Impact of extracellular matrix stiffness on genomic heterogeneity in MYCN -amplified neuroblastoma cell line
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RESEARCH
Open Access
Impact of extracellular matrix stiffness on genomic heterogeneity in MYCN-amplified neuroblastoma cell line Amparo López-Carrasco1,2, Susana Martín-Vañó1,2, Rebeca Burgos-Panadero1,2, Ezequiel Monferrer1,2, Ana P. Berbegall1,2, Beatriz Fernández-Blanco1, Samuel Navarro1,2 and Rosa Noguera1,2*
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 knockout 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 SHSY5Y 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. Keywords: Biotensegrity, Clonal selection, Stiffness, Vitronectin, Xenograft, 3D-bioprinting
Background Tumors are not homogeneous structures, but rather highly complex tissues involving many cell types, such as tumor, stromal and inflammatory cells [1–3]. Cells are primarily supported in solid tumors by the extracellular matrix (ECM), a three-dimensional (3D) dynamic network composed mainly of fibrous proteins, glycoproteins * Correspondence: [email protected] 1 Department of Pathology, Medical School, University of Valencia/INCLIVA, Valencia, Spain 2 CIBERONC, Madrid, Spain
and proteoglycans [1, 4]. In tumors, cells respond to the biochemical signals of their ECM, but also to physical forces such as tension (traction and compression forces that maintain their stability), known as biotensegrity [2]. In fact, increased stromal stiffness is a classic hallmark of cancer [1, 5], as is transformation of this stiffness into chemical signals through mechanotransduction for cell advantage [5–7]. Data suggest that an aberrant ECM may promote genetic instability and can even compromise DNA repair pathways necessary to prevent m
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