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2018 ; 8
(ä): 244
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Analysis of Hierarchical Organization in Gene Expression Networks Reveals
Underlying Principles of Collective Tumor Cell Dissemination and Metastatic
Aggressiveness of Inflammatory Breast Cancer
#MMPMID30023340
Tripathi S
; Jolly MK
; Woodward WA
; Levine H
; Deem MW
Front Oncol
2018[]; 8
(ä): 244
PMID30023340
show ga
Clusters 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.