Format:
1 Online-Ressource
Content:
Abstract: In colorectal cancers, the tumor microenvironment plays a key role in prognosis and therapy efficacy. Patient-derived tumor organoids (PDTO) show enormous potential for preclinical testing; however, cultured tumor cells lose important characteristics, including the consensus molecular subtypes (CMS). To better reflect the cellular heterogeneity, we established the colorectal cancer organoid–stroma biobank of matched PDTOs and cancer-associated fibroblasts (CAF) from 30 patients. Context-specific phenotyping showed that xenotransplantation or coculture with CAFs improves the transcriptomic fidelity and instructs subtype-specific stromal gene expression. Furthermore, functional profiling in coculture exposed CMS4-specific therapeutic resistance to gefitinib and SN-38 and prognostic expression signatures. Chemogenomic library screening identified patient- and therapy-dependent mechanisms of stromal resistance including MET as a common target. Our results demonstrate that colorectal cancer phenotypes are encrypted in the cancer epithelium in a plastic fashion that strongly depends on the context. Consequently, CAFs are essential for a faithful representation of molecular subtypes and therapy responses ex vivo
Note:
Cancer discovery. - 13, 10 (2023) , 2192-2211, ISSN: 2159-8290
Language:
English
DOI:
10.1158/2159-8290.cd-23-0050
URN:
urn:nbn:de:bsz:25-freidok-2389951
URL:
https://doi.org/10.1158/2159-8290.cd-23-0050
URL:
https://nbn-resolving.org/urn:nbn:de:bsz:25-freidok-2389951
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