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Isolation and Characterization of Tumor-initiating Cells from Sarcoma Patient-derived Xenografts
Published on: June 13, 2019
Primary intracranial sarcoma associated with DICER1 mutant: a case report and preclinical investigation
Hirokuni Honma1,2, Kensuke Tateishi3,4,5, Hiromichi Iwashita6,7
1Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa, Yokohama, 2360004, Japan.
Abstract:
Primary intracranial sarcoma (PIS) is a rare and aggressive pediatric brain tumor, which is partially associated with DICER1 mutant. Although the molecular genetic characteristics of this tumor have previously been investigated, novel therapeutic targets remain unclear. Further, the lack of faithful preclinical models has hampered the development of novel therapeutic strategies. Herein, we describe a pediatric case of PIS with DICER1 mutant and describe the development of the first novel patient-derived xenograft (PDX) model of this rare tumor. Somatic genomic profiling of the tumor revealed mutations in DICER1, TP53, and ATRX. Germline analysis further revealed a pathogenic variant of DICER1, significant for the diagnosis and management of hereditary tumor predisposition syndrome. Overall, we demonstrated that the PDX model faithfully retained the phenotype and genotype of the patient's tumor, as well as the DNA methylation profile. Through high-throughput drug screening using PDX tumor cells, we found that activation of the retinoic acid receptor (RAR) signaling pathway reduced tumor cell viability. These findings indicate that the RAR signaling pathway is a potential therapeutic target for PIS in DICER1 mutant.
Insights
This study details the first patient-derived xenograft model for pediatric primary intracranial sarcoma (PIS) with DICER1 mutations. Findings reveal the retinoic acid receptor (RAR) pathway as a potential therapeutic target for this rare brain tumor.
Area of Science:
- Pediatric oncology
- Neuro-oncology
- Genetics and genomics
Background:
- Primary intracranial sarcoma (PIS) is a rare, aggressive pediatric brain tumor.
- DICER1 mutations are associated with a subset of PIS cases.
- Lack of faithful preclinical models hinders therapeutic development for PIS.
Purpose of the Study:
- To describe a pediatric case of PIS with a DICER1 mutation.
- To develop and characterize the first patient-derived xenograft (PDX) model for PIS.
- To identify novel therapeutic targets for DICER1-mutant PIS.
Main Methods:
- Somatic and germline genomic profiling of patient tumor.
- Development and validation of a PDX model.
- High-throughput drug screening using PDX tumor cells.
Main Results:
- Genomic profiling identified mutations in DICER1, TP53, and ATRX.
- The PDX model accurately recapitulated the patient's tumor phenotype, genotype, and DNA methylation profile.
- Drug screening revealed that retinoic acid receptor (RAR) signaling pathway activation reduced tumor cell viability.
Conclusions:
- The developed PDX model serves as a valuable preclinical tool for PIS research.
- The RAR signaling pathway represents a promising therapeutic target for DICER1-mutant PIS.
- Germline DICER1 variants have implications for hereditary tumor predisposition syndromes.
