Abstract
A stage-associated gene expression signature of coordinately expressed genes, including the transcription factor Slug (SNAI2) and other epithelial-mesenchymal transition (EMT) markers has been found present in samples from publicly available gene expression datasets in multiple cancer types, including nonepithelial cancers. The expression levels of the co-expressed genes vary in a continuous and coordinate manner across the samples, ranging from absence of expression to strong co-expression of all genes. These data suggest that tumor cells may pass through an EMT-like process of mesenchymal transition to varying degrees. Here we show that, in glioblastoma multiforme (GBM), this signature is associated with time to recurrence following initial treatment. By analyzing data from The Cancer Genome Atlas (TCGA), we found that GBM patients who responded to therapy and had long time to recurrence had low levels of the signature in their tumor samples (P = 3×10−7). We also found that the signature is strongly correlated in gliomas with the putative stem cell marker CD44, and is highly enriched among the differentially expressed genes in glioblastomas vs. lower grade gliomas. Our results suggest that long delay before tumor recurrence is associated with absence of the mesenchymal transition signature, raising the possibility that inhibiting this transition might improve the durability of therapy in glioma patients.
Highlights
A multi-cancer stage-associated gene expression signature has recently been identified [1], consisting of a set of genes that are coordinately overexpressed only in samples of cancer that have exceeded a particular stage specific to each cancer type
In a recent experiment we confirmed that most of the genes of the signature, including a-SMA, are expressed in some xenografted human cancer cells themselves in vivo, but not in the host mouse cells [5]. These results indicate that cancer cells can pass through a mesenchymal transition process to varying degrees ranging from total lack of expression to strong co-expression of the genes of the signature, and the corresponding underlying pathways are activated within the cancer cells, in conjunction with other pathways in the tumor microenvironment providing contextual interactions
After doing exhaustive search among all 12,042 genes, the top ranked gene (EFEMP2) had rank sum equal to 75, still worse than that (70) of the metagene. These results suggest that the signature identified in [1] comprises a synergistic collection of genes corresponding to a biological mechanism of mesenchymal transition, which, when absent, is associated with increased time period to tumor recurrence in glioblastoma multiforme (GBM)
Summary
A multi-cancer stage-associated gene expression signature has recently been identified [1], consisting of a set of genes that are coordinately overexpressed only in samples of cancer that have exceeded a particular stage specific to each cancer type. In a recent experiment we confirmed that most of the genes of the signature, including a-SMA, are expressed in some xenografted human cancer cells themselves in vivo, but not in the host mouse cells [5]. These results indicate that cancer cells can pass through a mesenchymal transition process to varying degrees ranging from total lack of expression to strong co-expression of the genes of the signature, and the corresponding underlying pathways are activated within the cancer cells, in conjunction with other pathways in the tumor microenvironment providing contextual interactions
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