Analysis of Hierarchical Organization in Gene Expression Networks Reveals Underlying Principles of Collective Tumor Cell Dissemination and Metastatic Aggressiveness of Inflammatory Breast Cancer

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dc.citation.articleNumber244en_US
dc.citation.volumeNumber8en_US
dc.contributor.authorTripathi, Shubhamen_US
dc.contributor.authorJolly, Mohit Kumaren_US
dc.contributor.authorWoodward, Wendy A.en_US
dc.contributor.authorLevine, Herberten_US
dc.contributor.authorDeem, Michael W.en_US
dc.contributor.orgBioengineeringen_US
dc.contributor.orgPhysics and Astronomyen_US
dc.date.accessioned2018-11-01T14:28:11Zen_US
dc.date.available2018-11-01T14:28:11Zen_US
dc.date.issued2018en_US
dc.description.abstractClusters of circulating tumor cells (CTCs), despite being rare, may account for more than 90% of metastases. Cells in these clusters do not undergo a complete epithelial-to-mesenchymal transition (EMT), but retain some epithelial traits as compared to individually disseminating tumor cells. Determinants of single cell dissemination versus collective dissemination remain elusive. Inflammatory breast cancer (IBC), a highly aggressive breast cancer subtype that chiefly metastasizes via CTC clusters, is a promising model for studying mechanisms of collective tumor cell dissemination. Previous studies, motivated by a theory that suggests physical systems with hierarchical organization tend to be more adaptable, have found that the expression of metastasis-associated genes is more hierarchically organized in cases of successful metastases. Here, we used the cophenetic correlation coefficient (CCC) to quantify the hierarchical organization in the expression of two distinct gene sets, collective dissemination-associated genes and IBC-associated genes, in cancer cell lines and in tumor samples from breast cancer patients. Hypothesizing that a higher CCC for collective dissemination-associated genes and for IBC-associated genes would be associated with retention of epithelial traits enabling collective dissemination and with worse disease progression in breast cancer patients, we evaluated the correlation of CCC with different phenotypic groups. The CCC of both the abovementioned gene sets, the collective dissemination-associated genes and the IBC-associated genes, was higher in (a) epithelial cell lines as compared to mesenchymal cell lines and (b) tumor samples from IBC patients as compared to samples from non-IBC breast cancer patients. A higher CCC of both gene sets was also correlated with a higher rate of metastatic relapse in breast cancer patients. In contrast, neither the levels of CDH1 gene expression nor gene set enrichment analysis (GSEA) of the abovementioned gene sets could provide similar insights. These results suggest that retention of some epithelial traits in disseminating tumor cells as IBC progresses promotes successful breast cancer metastasis. The CCC provides additional information regarding the organizational complexity of gene expression in comparison to GSEA. We have shown that the CCC may be a useful metric for investigating the collective dissemination phenotype and a prognostic factor for IBC.en_US
dc.identifier.citationTripathi, Shubham, Jolly, Mohit Kumar, Woodward, Wendy A., et al.. "Analysis of Hierarchical Organization in Gene Expression Networks Reveals Underlying Principles of Collective Tumor Cell Dissemination and Metastatic Aggressiveness of Inflammatory Breast Cancer." 8, (2018) Frontiers: https://doi.org/10.3389/fonc.2018.00244.en_US
dc.identifier.digitalfonc-08-00244en_US
dc.identifier.doihttps://doi.org/10.3389/fonc.2018.00244en_US
dc.identifier.urihttps://hdl.handle.net/1911/103270en_US
dc.language.isoengen_US
dc.publisherFrontiersen_US
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subject.keywordcollective disseminationen_US
dc.subject.keywordinflammatory breast canceren_US
dc.subject.keywordepithelial-to-mesenchymal transitionen_US
dc.subject.keywordhierarchyen_US
dc.subject.keywordhybrid E/Men_US
dc.subject.keywordcophenetic correlation coefficienten_US
dc.titleAnalysis of Hierarchical Organization in Gene Expression Networks Reveals Underlying Principles of Collective Tumor Cell Dissemination and Metastatic Aggressiveness of Inflammatory Breast Canceren_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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