Stromal contribution to the colorectal cancer transcriptome

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• A poor-prognosis stem/serrated/mesenchymal (SSM) transcriptional subtype of colorectal cancer (CRC) has been identified.
• Genes upregulated in this subtype are also expressed by stromal cells, suggesting a non-epithelial origin.

Purpose of the Study:

• To investigate the cellular origin of the SSM transcriptional signature in colorectal cancer.
• To determine the association between stromal cell abundance and the SSM subtype's clinical features.

Main Methods:

• Analysis of colorectal cancer expression data from patient-derived xenografts.
• Species-specific mRNA expression analysis to differentiate human and mouse gene expression.
• Utilized transcriptional signatures for cancer-associated fibroblasts (CAFs), leukocytes, and endothelial cells.

Main Results:

• SSM gene mRNA levels in xenografts were predominantly attributed to stromal expression.
• Human CRC samples of the SSM subtype showed significantly higher expression of CAF, leukocyte, and endothelial cell signatures.
• High CAF signature expression correlated with poor prognosis in untreated CRC.
• Combined high stromal signature expression predicted radiotherapy resistance in rectal cancer.

Conclusions:

• The distinctive transcriptional and clinical features of the SSM colorectal cancer subtype are attributable to its abundant stromal component.
• Stromal cell abundance, particularly CAFs, is a key determinant of the SSM subtype's poor prognosis and treatment resistance.