The DOI matches its Crossref record; 69 of the 69 references it cites were found in a registry or an index.
Colorectal cancer organoid-stroma biobank allows subtype-specific assessment of individualized therapy responses
Open accessPublished version of a preprint
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. Significance: Systematic characterization of the organoid–stroma biobank provides a resource for context dependency in colorectal cancer. We demonstrate a colorectal cancer subtype memory of PDTOs that is independent of specific driver mutations. Our data underscore the importance of functional profiling in cocultures for improved preclinical testing and identification of stromal resistance mechanisms. This article is featured in Selected Articles from This Issue, p. 2109
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“A very recent study reported that coculture with CAFs promotes an increased resistance to SN-38 (irinotecan active metabolite) and gefitinib of CMS4 compared with CMS2 patient-derived tumor organoids (53).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [53]
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“studies based on coculture experiments have unambiguously demonstrated that CAFs reinforce the CMS4 traits of cancer cells (53).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [53]
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Metadata
- Authors
- Farin, H. F., Mosa, M. H., Ndreshkjana, B., Grebbin, B. M., Ritter, B., Menche, C., Kennel, K. B., Ziegler, P. K., Szabó, L., Bollrath, J., Rieder, D., Michels, B. E., Kress, A., Bozlar, M., Darvishi, T., Stier, S., Kur, I.-M., Bankov, K., Kesselring, R., Fichtner-Feigl, S., Brüne, B., Goetze, T. O., Al-Batran, S.-E., Brandts, C. H., Bechstein, W. O., Wild, P. J., Weigert, A., Müller, S., Knapp, S., Trajanoski, Z., & Greten, F. R.
- Affiliations
- Goethe University Frankfurt (DE)
- Georg Speyer Haus (DE)
- Innsbruck Medical University (AT)
- University of Freiburg (DE)
- 8Department of General and Visceral Surgery, University of Freiburg, Freiburg, Germany.
- Institute of Clinical Cancer Research (DE)
- 9Institute of Clinical Cancer Research IKF, Frankfurt am Main, Germany.
- Corresponding author
- Farin, Henner F.
- Greten, Florian R.
- ORCID
- Farin, Henner F.
- Mosa, Mohammed H.
- Ndreshkjana, Benardina
- Grebbin, Britta M.
- Ritter, Birgit
- Menche, Constantin
- Kennel, Kilian B.
- Ziegler, Paul K.
- Szabó, Lili
- Bollrath, Julia
- Rieder, Dietmar
- Michels, Birgitta E.
- Kress, Alena
- Bozlar, Müge
- Darvishi, Tahmineh
- Stier, Sara
- Kur, Ivan-Maximilano
- Bankov, Katrin
- Kesselring, Rebecca
- Fichtner-Feigl, Stefan
- Brüne, Bernhard
- Goetze, Thorsten O.
- Al-Batran, Salah-Eddin
- Brandts, Christian H.
- Bechstein, Wolf O.
- Wild, Peter J.
- Weigert, Andreas
- Müller, Susanne
- Knapp, Stefan
- Trajanoski, Zlatko
- Greten, Florian R.
- Venue
- Cancer Discovery
- Published
- 2023-07-25
- Volume
- 13
- Issue
- 10
- Pages
- 2192-2211
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC10551667
- OpenAlex
- W4385230305
- Cited by
- 120
- References
- 69
- Citations by year
- 2026: 39 · 2025: 44 · 2024: 31 · 2023: 6
- FWCI
- 14.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Discovery (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- LOEWE Center Frankfurt Cancer Institute (III L 5 - 519/03/03.001 - (0015))
- Deutsche Forschungsgemeinschaft (FOR2438 - FA1334/2-2)
- HORIZON EUROPE European Research Council (Advanced Grant PLASTICAN-101021078)
- Innovative Medicines Initiative 2 (EUbOPEN grant n°, 875510)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- colorectal cancer, patient-derived tumor organoids, cancer-associated fibroblasts, consensus molecular subtypes, tumor microenvironment, gefitinib resistance, MET, xenotransplantation, co-culture, preclinical drug testing
- MeSH terms
- Cancer-Associated Fibroblasts, Humans, Organoids, Tumor Cells, Cultured, Colorectal Neoplasms, Biological Specimen Banks, Tumor Microenvironment
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