WES of Colorectal cancer organoid-stroma biobank cohort

In colorectal cancers (CRC) the tumor microenvironment plays a key role for prognosis and therapy efficacy. Patient-derived tumor organoids (PDTOs) show enormous potential for preclinical testing, however, in purely epithelial cultures features including the ‘consensus molecular subtypes’ (CMS) are largely eradicated. To better reflect cell heterogeneity, we established the CRC organoid-stroma biobank of matched PDTOs and cancer-associated fibroblasts (CAFs) from 30 patients. Context-specific phenotyping showed that xenotransplantation or co-culture with CAFs restores the individual transcriptomic status and instructs subtype-specific stromal gene expression. Furthermore, co-culture exposed CMS4-specific resistance to Gefitinib and SN-38 and revealed prognostic gene expression signatures. Chemogenomic library screening identified patient- and therapy-dependent mechanisms of stromal resistance including MET as common target. Our results demonstrate that CRC phenotypes are encrypted in the cancer epithelium in a plastic fashion that strongly depends on the context. Consequently, CAFs are essential for faithful representation of molecular subtypes and therapy responses ex vivo.EGA study EGAS00001007301