Abstract
AbstractTumors become invasive by penetrating adjacent connective tissue, but the underlying biological mechanisms remain obscure. We recently identified a precise gene expression signature of fibroblastic origin associated with cancer invasion, the first step of the metastatic cascade. The signature contains many coordinately overexpressed genes, prominent among which are COL11A1, THBS2 and INHBA. Here we show that there is a striking similarity between the set of expressed genes in this metastasis-associated fibroblastic (MAF) signature and the set of genes that are downregulated when fibroblasts are reprogrammed to induced pluripotent stem cells (iPSCs). Because it is known that fibroblast reprogramming involves a mesenchymal epithelial transition (MET), the above facts suggest that, conversely, the metastasis-associated fibroblasts responsible for the signature may result from stem-like cells undergoing some type of epithelial-mesenchymal transition (EMT). Therefore, we speculate that cancer stem cells (CSCs) undergoing some type of EMT become fibroblastic to obtain motility and invasiveness, reactivating early embryonic developmental pathways, and that these fibroblast-like cells are the main source of the MAF signature that we previously identified.
Highlights
We recently identified and reported [1] a precise gene expression signature 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
Among all signatures that we searched outside cancer datasets, we found by far the largest enrichment to be present in the set of genes that are downregulated in induced pluripotent stem cells as well as embryonic stem cells (ESCs) compared to the fibroblasts before reprogramming
Consistent with the discovery of the metastasis-associated fibroblastic (MAF) signature [1], four of these sets correspond to genes upregulated in high-stage vs. low-stage cancer samples, in lobular breast cancer, gastric cancer, ductal breast cancer, and papillary thyroid cancer
Summary
We recently identified and reported [1] a precise gene expression signature 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 (a previous version available in Nature Precedings at http://hdl.handle.net/10101/npre.2010.4503.1). In each rich cancer dataset, but not in non-cancer datasets, finding the list of genes whose expression is most correlated with that of COL11A1 consistently identifies the other genes of the signature as a result of the presence of those high-stage samples that contain it. The signature contains several transcription factors associated with epithelial-mesenchymal transition (EMT), slug (SNAI2). It does not contain snail (SNAI1), which we found, at least in ovarian cancer, to be methylated
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