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The gene-activity subtype with the worst prognosis turned out not to be a property of the cancer cells at all. Growing human tumours in mice showed that its defining genes are switched on in the surrounding connective tissue.
Genes upregulated in the poor-prognosis stem, serrated and mesenchymal transcriptional subtype are also prominently expressed by stromal cells, raising the possibility that the transcripts derive from stroma rather than epithelial cancer cells. Colorectal cancer expression data from patient-derived xenografts, where mouse stroma supports human cancer cells, allowed species-specific expression analysis, which showed that the subtype's messenger RNA levels were mostly due to stromal expression. Transcriptional signatures built to report the abundance of cancer-associated fibroblasts, leukocytes or endothelial cells were all significantly higher in human samples of that subtype. High fibroblast signature expression was associated with poor prognosis in untreated disease, and joint high expression of the stromal signatures predicted resistance to radiotherapy in rectal cancer.
It means a CMS4 call on a bulk sample partly measures how much stroma was in the block, which is both a caution for the classification and a pointer to the stroma as the thing to treat.
Shares Consensus molecular subtypes (CMS1-4), Nature Genetics, Desmoplasia (tumour stroma), Fibroblast activation, desmoplasia & matrix stiffness.
Shares Nature Genetics, Desmoplasia (tumour stroma), Fibroblast activation, desmoplasia & matrix stiffness, Tumour microenvironment (TME).
Shares Fibroblast activation, desmoplasia & matrix stiffness, Tumour microenvironment (TME), RNA sequencing & expression profiling.
Shares Consensus molecular subtypes (CMS1-4), Desmoplasia (tumour stroma), RNA sequencing & expression profiling, Colorectal cancer.
Shares Desmoplasia (tumour stroma), Fibroblast activation, desmoplasia & matrix stiffness, Tumour microenvironment (TME).
Shares Desmoplasia (tumour stroma), Fibroblast activation, desmoplasia & matrix stiffness, Tumour microenvironment (TME).
Shares Desmoplasia (tumour stroma), Fibroblast activation, desmoplasia & matrix stiffness, Tumour microenvironment (TME).
Shares Desmoplasia (tumour stroma), Fibroblast activation, desmoplasia & matrix stiffness, Tumour microenvironment (TME).