Stromal contribution to the colorectal cancer transcriptome

Nat Genet. 2015 Apr;47(4):312-9. doi: 10.1038/ng.3224. Epub 2015 Feb 23.

Abstract

Recent studies identified a poor-prognosis stem/serrated/mesenchymal (SSM) transcriptional subtype of colorectal cancer (CRC). We noted that genes upregulated in this subtype are also prominently expressed by stromal cells, suggesting that SSM transcripts could derive from stromal rather than epithelial cancer cells. To test this hypothesis, we analyzed CRC expression data from patient-derived xenografts, where mouse stroma supports human cancer cells. Species-specific expression analysis showed that the mRNA levels of SSM genes were mostly due to stromal expression. Transcriptional signatures built to specifically report the abundance of cancer-associated fibroblasts (CAFs), leukocytes or endothelial cells all had significantly higher expression in human CRC samples of the SSM subtype. High expression of the CAF signature was associated with poor prognosis in untreated CRC, and joint high expression of the stromal signatures predicted resistance to radiotherapy in rectal cancer. These data show that the distinctive transcriptional and clinical features of the SSM subtype can be ascribed to its particularly abundant stromal component.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Epithelial-Mesenchymal Transition / genetics
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Gene Expression Regulation, Neoplastic
  • Heterografts
  • Humans
  • Mice
  • Microarray Analysis
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Transcriptome*

Substances

  • Biomarkers, Tumor

Associated data

  • GEO/GSE56695
  • GEO/GSE56699