Abstract
Abstract Recent studies have identified a stem/serrated/mesenchymal (SSM) molecular subtype of colorectal cancer (CRC) that is associated with poor prognosis. We noted that genes upregulated in this subtype are also prominently expressed by stromal cells. This led us to hypothesize that the SSM transcripts could derive from the tumor microenvironment, rather than being intrinsic to cancer cells. To test this hypothesis, we analyzed microarray and RNAseq expression data from patient-derived xenografts (PDXs) of CRC, where human cancer cells are supported by murine stroma. Species-specific expression analysis revealed that mRNA levels of SSM genes are mostly due to stromal expression. Considering only genes exclusively expressed by stromal cells in PDXs, We then built three expression signatures specifically reporting the abundance of cancer-associated fibroblasts (CAFs), leucocytes or endothelial cells. In human CRC samples, all stromal signatures were strongly associated with the SSM subtype. A high CAF signature was associated with poor prognosis in untreated CRC patients, while in rectal cancer high stromal signatures jointly predicted radioresistance. These data show that the distinctive transcriptional and clinical features of the SSM subtype can be ascribed to its particularly abundant stroma. Citation Format: Claudio Isella, Andrea Terrasi, Sara E. Bellomo, Consalvo Petti, Andrea Muratore, Alfredo Mellano, Mark De Ridder, Paola Cassoni, Guy Storme, Andrea Bertotti, Enzo Medico. Stromal contribution to the colorectal cancer transcriptome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4760. doi:10.1158/1538-7445.AM2015-4760
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