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Updated: Aug 21, 2026
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Published on: December 23, 2022
Patient-Derived Organoid and Single-Cell Multiomics Reveal Evolution Driven by CEACAM6/KRT19-Mediated Heterogeneity
Changwen Jing1, Zhuo Wang1, Haixia Cao1
1Molecular Pathology Laboratory, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
Abstract:
Colorectal cancer (CRC) remains a leading cause of cancer mortality globally, with therapeutic efficacy hindered by tumor heterogeneity and drug resistance. While organoid technology offers unprecedented opportunities to model tumor complexity, systematic platforms for chemo-targeted combination screening and molecular mechanisms underlying chemoresistance remain underexplored in Chinese populations. Here, we established a biobank of 17 patient-derived CRC organoids (85% success rate) from treatment-naïve surgical specimens, preserving histopathological fidelity and molecular diversity of parental tumors. High-throughput drug screening across eight clinical regimens revealed different responses. To dissect chemoresistance mechanisms, six organoids representing extreme phenotypes (three sensitive and three resistant, based on IC50 difference for irinotecan + raltitrexed) were selected from this cohort for single-cell transcriptomic analysis. Single-cell transcriptomics of irinotecan + raltitrexed-treated organoids identified chemoresistance-associated clonal expansion of epithelial subpopulations (cluster_0), characterized by overexpression of REG4/TFF1/TFF3 and epithelial keratins (KRT19/KRT8/KRT18). Intercellular network analysis revealed intra-epithelial communication as a resistance hub, mediated by 32 ligand-receptor pairs. Integration with TCGA-COAD cohort (n = 378) demonstrated intratumoral heterogeneity (ITH) score as an independent prognostic determinant, outperforming stemness/angiogenesis metrics. Machine learning consensus identified CEACAM6 and KRT19 as dual regulators of mortality and ITH through epithelial plasticity networks. Our multi-omics framework establishes organoid-guided chemoresistance mechanisms while proposing ITH quantification targeting as precision strategies. This study bridges critical gaps in CRC therapeutic personalization, offering clinically actionable insights for overcoming treatment failure.
Insights
Patient-derived colorectal cancer organoids reveal mechanisms of chemoresistance. Intratumoral heterogeneity predicts prognosis, offering new precision treatment strategies for colorectal cancer.
Area of Science:
- Oncology
- Genomics
- Biotechnology
Background:
- Colorectal cancer (CRC) is a major global health concern, with treatment limited by tumor heterogeneity and drug resistance.
- Existing models inadequately address chemoresistance mechanisms and drug screening in Chinese populations.
Purpose of the Study:
- To establish and characterize patient-derived colorectal cancer organoids for drug screening.
- To investigate molecular mechanisms of chemoresistance using single-cell transcriptomics.
- To identify prognostic biomarkers and therapeutic targets for colorectal cancer.
Main Methods:
- Established a biobank of 17 patient-derived CRC organoids.
- Performed high-throughput drug screening across eight clinical regimens.
- Conducted single-cell transcriptomic analysis on selected organoids.
- Integrated data with The Cancer Genome Atlas (TCGA) cohort.
Main Results:
- Organoids preserved histopathological and molecular features of parental tumors.
- Identified chemoresistance-associated epithelial subpopulations with specific gene overexpression (REG4/TFF1/TFF3, KRT19/KRT8/KRT18).
- Discovered intra-epithelial communication as a resistance mechanism.
- Demonstrated intratumoral heterogeneity (ITH) score as an independent prognostic factor.
- Identified CEACAM6 and KRT19 as regulators of mortality and ITH.
Conclusions:
- Patient-derived organoids provide a robust platform for studying colorectal cancer chemoresistance.
- ITH quantification is a promising strategy for precision medicine in colorectal cancer.
- This framework offers actionable insights for overcoming treatment failure in colorectal cancer.