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Isolation and Characterization of Tumor-initiating Cells from Sarcoma Patient-derived Xenografts
Published on: June 13, 2019
Reconstruction of T cell infiltration in an osteosarcoma PDX-organoid interactive biobank for personalized
Wei Sun1, Yining Tao1, Xin He1
1Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China.
Abstract:
Osteosarcoma (OS) is an aggressive malignant bone tumor with limited therapeutic options and low response to immunotherapy. OS rarity slows clinical translation, highlighting the need for models that bridge patient-derived xenograft (PDX) systems and next-generation platforms. Here, we establish an OS PDX-organoid interactive biobank by self-assembling single-cell suspensions into individualized OS organoids (iOSs). iOS models recapitulate OS spatial and architectural features at millimeter scale in vitro and as xenografts and maintain functional pairing with matched PDX models. We validate iOS fidelity using histopathology, spatial features, genomics, transcriptomics, and pharmacogenomics. By reconstructing T cell infiltration in PDX-derived iOS models, we model treatment-associated immune responses and support immunotherapy translational studies. Using paired iOS-PDX models, we show that a PRMT5MTA inhibitor enhances immunotherapy response in chromosome 9p21.3-deleted OS.
Insights
We developed novel osteosarcoma organoid models (iOSs) that mimic patient tumors. These models show a PRMT5 inhibitor improves immunotherapy response in specific osteosarcoma subtypes.
Area of Science:
- Oncology
- Biotechnology
- Genomics
Background:
- Osteosarcoma (OS) is an aggressive bone cancer with poor therapeutic outcomes and limited immunotherapy efficacy.
- The rarity of OS hinders clinical translation, necessitating advanced preclinical models.
- Patient-derived xenograft (PDX) models offer clinical relevance but lack the scalability of organoid systems.
Purpose of the Study:
- To establish a novel osteosarcoma patient-derived xenograft-organoid (PDX-organoid) interactive biobank.
- To create individualized osteosarcoma organoids (iOSs) that recapitulate tumor architecture and function.
- To utilize these models for evaluating novel therapeutic strategies, including immunotherapy combinations.
Main Methods:
- Self-assembly of single-cell suspensions into individualized osteosarcoma organoids (iOSs).
- Validation of iOS fidelity through histopathology, spatial analysis, genomics, transcriptomics, and pharmacogenomics.
- Reconstruction of T cell infiltration in PDX-derived iOS models to study immune responses.
Main Results:
- iOS models successfully recapitulated the spatial and architectural features of OS at a millimeter scale.
- iOS models maintained functional pairing with matched PDX models, confirmed by multi-omics analyses.
- Paired iOS-PDX models demonstrated that a PRMT5 inhibitor enhances immunotherapy response in chromosome 9p21.3-deleted OS.
Conclusions:
- The established OS PDX-organoid interactive biobank provides a powerful platform for preclinical research.
- iOS models serve as a bridge between PDX systems and next-generation platforms, facilitating translational studies.
- This platform supports the development of effective immunotherapy strategies for osteosarcoma, particularly in specific genetic subtypes.
