A systems biology approach reveals common metastatic pathways in osteosarcoma
Author
Flores, RicardoLi, Yiting
Yu, Alexander
Shen, Jianhe
Rao, Pulivarthi
Lau, Serrine
Vannucci, Marina
Lau, Ching
Man, Tsz-Kwong
Affiliation
Texas Children’s Cancer and Hematology Centers, Texas Children’s Hospital, Houston, TX, USADepartment of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
Southwest Environmental Health Science Centers, The University of Arizona, Tucson, AZ, USA
Department of Statistics, Rice University, Houston, TX, USA
Issue Date
2012
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BioMed CentralCitation
Flores et al. BMC Systems Biology 2012, 6:50 http://www.biomedcentral.com/1752-0509/6/50Journal
BMC Systems BiologyRights
© 2012 Flores et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).Collection Information
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.Abstract
BACKGROUND:Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. The survival rate of patients with metastatic disease remains very dismal. Nevertheless, metastasis is a complex process and a single-level analysis is not likely to identify its key biological determinants. In this study, we used a systems biology approach to identify common metastatic pathways that are jointly supported by both mRNA and protein expression data in two distinct human metastatic OS models.RESULTS:mRNA expression microarray and N-linked glycoproteomic analyses were performed on two commonly used isogenic pairs of human metastatic OS cell lines, namely HOS/143B and SaOS-2/LM7. Pathway analysis of the differentially regulated genes and glycoproteins separately revealed pathways associated to metastasis including cell cycle regulation, immune response, and epithelial-to-mesenchymal-transition. However, no common significant pathway was found at both genomic and proteomic levels between the two metastatic models, suggesting a very different biological nature of the cell lines. To address this issue, we used a topological significance analysis based on a "shortest-path" algorithm to identify topological nodes, which uncovered additional biological information with respect to the genomic and glycoproteomic profiles but remained hidden from the direct analyses. Pathway analysis of the significant topological nodes revealed a striking concordance between the models and identified significant common pathways, including "Cytoskeleton remodeling/TGF/WNT", "Cytoskeleton remodeling/Cytoskeleton remodeling", and "Cell adhesion/Chemokines and adhesion". Of these, the "Cytoskeleton remodeling/TGF/WNT" was the top ranked common pathway from the topological analysis of the genomic and proteomic profiles in the two metastatic models. The up-regulation of proteins in the "Cytoskeleton remodeling/TGF/WNT" pathway in the SaOS-2/LM7 and HOS/143B models was further validated using an orthogonal Reverse Phase Protein Array platform.CONCLUSIONS:In this study, we used a systems biology approach by integrating genomic and proteomic data to identify key and common metastatic mechanisms in OS. The use of the topological analysis revealed hidden biological pathways that are known to play critical roles in metastasis. Wnt signaling has been previously implicated in OS and other tumors, and inhibitors of Wnt signaling pathways are available for clinical testing. Further characterization of this common pathway and other topological pathways identified from this study may lead to a novel therapeutic strategy for the treatment of metastatic OS.EISSN
1752-0509Version
Final published versionAdditional Links
http://www.biomedcentral.com/1752-0509/6/50ae974a485f413a2113503eed53cd6c53
10.1186/1752-0509-6-50
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Except where otherwise noted, this item's license is described as © 2012 Flores et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).