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Colorectal Cancer Organoid-Stroma Biobank Allows Subtype-Specific Assessment of Individualized Therapy Responses
Henner F Farin1,2,3,4, Mohammed H Mosa1,2, Benardina Ndreshkjana1,2
1Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
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.
Insights
Patient-derived tumor organoids (PDTOs) better mimic colorectal cancer (CRC) when cultured with cancer-associated fibroblasts (CAFs). This organoid-stroma model reveals context-dependent CRC subtypes and therapy resistance mechanisms.
Area of Science:
- Oncology
- Cancer Biology
- Translational Research
Background:
- The tumor microenvironment significantly impacts colorectal cancer (CRC) prognosis and treatment effectiveness.
- Patient-derived tumor organoids (PDTOs) are promising for preclinical studies but often lose critical characteristics like consensus molecular subtypes (CMS) in culture.
- Understanding context-dependent cellular behavior is crucial for accurate CRC modeling.
Purpose of the Study:
- To establish a colorectal cancer organoid-stroma biobank to better reflect tumor heterogeneity.
- To investigate the role of cancer-associated fibroblasts (CAFs) in maintaining PDTO fidelity and subtype characteristics.
- To identify context-specific therapeutic resistance mechanisms and potential drug targets in CRC.
Main Methods:
- Established a biobank of matched PDTOs and CAFs from 30 CRC patients.
- Performed context-specific phenotyping, including transcriptomic analysis and coculture experiments.
- Utilized functional profiling, chemogenomic library screening, and xenotransplantation.
Main Results:
- Coculture with CAFs or xenotransplantation improved transcriptomic fidelity and induced subtype-specific stromal gene expression in PDTOs.
- Functional profiling in coculture identified CMS4-specific resistance to gefitinib and SN-38.
- Identified MET as a common target for stromal resistance mechanisms, dependent on patient and therapy context.
Conclusions:
- Colorectal cancer phenotypes are plastic and highly context-dependent, influenced by the tumor microenvironment.
- CAFs are essential for accurately representing molecular subtypes and predicting therapy responses in ex vivo models.
- The organoid-stroma biobank serves as a valuable resource for studying context dependency in CRC and improving preclinical testing.
