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Patient-derived d-MMR/MSI phenotype urachal cancer organoids for personalized drug screening
Kuangen Zhang1, Xinyi Li2, Zhenting Zhang3
1Translational Cancer Research Center, First Hospital, Peking University, Beijing, China.
Background:
Urachal cancer (UrC) is a rare, aggressive malignancy typically diagnosed at advanced stages, where systemic treatment becomes necessary. However, cytotoxic chemotherapy offers limited efficacy, and prospective clinical trials are exceedingly difficult due to the rarity of the disease. Thus, robust in vitro models are urgently needed to support precision medicine approaches for UrC.
Methods:
Fresh UrC tumor samples were collected from patients undergoing en bloc resection and cultured to generate PDOs. These organoids were subjected to drug screening using standard chemotherapeutic agents. Whole-exome sequencing (WES) and RNA sequencing (RNA-seq) were conducted to compare the molecular profiles of the PDOs with their corresponding parental tumors. Associations between drug responses and genomic/transcriptomic features were analyzed. Student's t-test was used for statistical assessment.
Results:
The established d-MMR/MSI phenotype UrC PDOs faithfully reproduced the genomic and transcriptomic landscapes of the original tumors, including intratumoral heterogeneity, and demonstrated consistent drug response profiles. Molecular characterization further revealed actionable targets within the RAS/MAPK and PI3K/AKT/mTOR pathways, as well as immune-related targets such as PD-L1. These findings highlight the utility of PDOs in modeling rare cancers and guiding personalized therapeutic strategies.
Conclusions:
d-MMR/MSI phenotype UrC PDOs recapitulate the phenotypic and molecular features of their parental tumors, capturing critical heterogeneity. As such, they represent a valuable platform for reflecting treatment responses, investigating resistance mechanisms, and developing individualized therapeutic regimens.
Insights
Patient-derived organoids (PDOs) from rare urachal cancer (UrC) models tumor heterogeneity and drug responses. These models are crucial for developing precision medicine strategies for UrC.
Area of Science:
- Oncology
- Cancer Research
- Translational Medicine
Background:
- Urachal cancer (UrC) is a rare and aggressive malignancy often diagnosed at advanced stages.
- Limited efficacy of current chemotherapy and difficulty in conducting clinical trials necessitate better in vitro models.
- Robust models are essential for advancing precision medicine in UrC.
Purpose of the Study:
- To develop and characterize patient-derived organoids (PDOs) from urachal cancer (UrC) for in vitro modeling.
- To assess the utility of UrC PDOs in predicting drug responses and identifying therapeutic targets.
- To evaluate PDOs as a platform for precision medicine in rare cancers.
Main Methods:
- Established urachal cancer (UrC) patient-derived organoids (PDOs) from fresh tumor samples.
- Performed drug screening on PDOs using standard chemotherapeutic agents.
- Conducted whole-exome sequencing (WES) and RNA sequencing (RNA-seq) for molecular profiling and comparison with parental tumors.
Main Results:
- UrC PDOs with d-MMR/MSI phenotype accurately replicated the genomic and transcriptomic profiles of original tumors, including heterogeneity.
- PDOs demonstrated consistent drug response patterns.
- Identified actionable targets in RAS/MAPK and PI3K/AKT/mTOR pathways, and immune targets like PD-L1.
Conclusions:
- d-MMR/MSI phenotype UrC PDOs serve as valuable models that recapitulate tumor features and heterogeneity.
- These organoids are effective platforms for predicting treatment responses and investigating resistance mechanisms.
- UrC PDOs facilitate the development of individualized therapeutic strategies for rare cancers.
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