Single‐cell transcriptomic sequencing identifies subcutaneous patient‐derived xenograft recapitulated medulloblastoma
Jiayu Gao, Yahui Zhao, Ziwei Wang, Fei Liu, Xuan Chen, Jialin Mo, Yifei Jiang, Yongqiang Liu, Peiyi Tian, Yanong Li, Kaiwen Deng, Xueling Qi, Dongming Han, Zijia Liu, Zhengtao Yang, Yixi Chen, Yujie Tang, Chunde Li, Hailong Liu, Jiankang Li, Tao Jiang- Medical Laboratory Technology
- Veterinary (miscellaneous)
- Molecular Biology
- Biochemistry
- Medicine (miscellaneous)
Abstract
Background
Medulloblastoma (MB) is one of the most common malignant brain tumors that mainly affect children. Various approaches have been used to model MB to facilitate investigating tumorigenesis. This study aims to compare the recapitulation of MB between subcutaneous patient‐derived xenograft (sPDX), intracranial patient‐derived xenograft (iPDX), and genetically engineered mouse models (GEMM) at the single‐cell level.
Methods
We obtained primary human sonic hedgehog (SHH) and group 3 (G3) MB samples from six patients. For each patient specimen, we developed two sPDX and iPDX models, respectively. Three Patch+/− GEMM models were also included for sequencing. Single‐cell RNA sequencing was performed to compare gene expression profiles, cellular composition, and functional pathway enrichment. Bulk RNA‐seq deconvolution was performed to compare cellular composition across models and human samples.
Results
Our results showed that the sPDX tumor model demonstrated the highest correlation to the overall transcriptomic profiles of primary human tumors at the single‐cell level within the SHH and G3 subgroups, followed by the GEMM model and iPDX. The GEMM tumor model was able to recapitulate all subpopulations of tumor microenvironment (TME) cells that can be clustered in human SHH tumors, including a higher proportion of tumor‐associated astrocytes and immune cells, and an additional cluster of vascular endothelia when compared to human SHH tumors.
Conclusions
This study was the first to compare experimental models for MB at the single‐cell level, providing value insights into model selection for different research purposes. sPDX and iPDX are suitable for drug testing and personalized therapy screenings, whereas GEMM models are valuable for investigating the interaction between tumor and TME cells.