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PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma
Kirsi Toivanen1, Sami Kilpinen2, Kalle Ojala3
1Department of Pathology, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland.
Abstract:
Liposarcomas (LPSs) are a heterogeneous group of malignancies that arise from adipose tissue. Although LPSs are among the most common soft-tissue sarcoma subtypes, precision medicine treatments are not currently available. To discover LPS-subtype-specific therapy targets, we investigated RNA sequenced transcriptomes of 131 clinical LPS tissue samples and compared the data with a transcriptome database that contained 20,218 samples from 95 healthy tissues and 106 cancerous tissue types. The identified genes were referred to the NCATS BioPlanet library with Enrichr to analyze upregulated signaling pathways. PDE3A protein expression was investigated with immunohistochemistry in 181 LPS samples, and PDE3A and SLFN12 mRNA expression with RT-qPCR were investigated in 63 LPS samples. Immunoblotting and cell viability assays were used to study LPS cell lines and their sensitivity to PDE3A modulators. We identified 97, 247, and 37 subtype-specific, highly expressed genes in dedifferentiated, myxoid, and pleomorphic LPS subtypes, respectively. Signaling pathway analysis revealed a highly activated hedgehog signaling pathway in dedifferentiated LPS, phospholipase c mediated cascade and insulin signaling in myxoid LPS, and pathways associated with cell proliferation in pleomorphic LPS. We discovered a strong association between high PDE3A expression and myxoid LPS, particularly in high-grade tumors. Moreover, myxoid LPS samples showed elevated expression levels of SLFN12 mRNA. In addition, PDE3A- and SLFN12-coexpressing LPS cell lines SA4 and GOT3 were sensitive to PDE3A modulators. Our results indicate that PDE3A modulators are promising drugs to treat myxoid LPS. Further studies are required to develop these drugs for clinical use.
Insights
Researchers identified potential new treatments for liposarcomas (LPSs), a common soft-tissue cancer. They found that PDE3A modulators show promise for treating myxoid LPS, a specific subtype, by targeting key gene expressions and pathways.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Liposarcomas (LPSs) are common soft-tissue sarcomas lacking precision medicine treatments.
- Identifying subtype-specific therapeutic targets is crucial for advancing LPS treatment.
Purpose of the Study:
- To discover LPS subtype-specific therapy targets by analyzing transcriptomes and signaling pathways.
- To investigate the role of PDE3A and SLFN12 in LPS, particularly myxoid LPS.
Main Methods:
- RNA sequencing of 131 clinical LPS samples compared with a large transcriptome database.
- BioPlanet library and Enrichr for signaling pathway analysis.
- Immunohistochemistry, RT-qPCR, immunoblotting, and cell viability assays to assess PDE3A and SLFN12.
Main Results:
- Identified 97, 247, and 37 subtype-specific highly expressed genes in dedifferentiated, myxoid, and pleomorphic LPS, respectively.
- Dedifferentiated LPS showed activated hedgehog signaling; myxoid LPS showed phospholipase C and insulin signaling.
- High PDE3A expression strongly associated with myxoid LPS; elevated SLFN12 mRNA observed in myxoid LPS.
Conclusions:
- PDE3A modulators are promising therapeutic agents for myxoid LPS.
- Coexpression of PDE3A and SLFN12 in LPS cell lines indicates sensitivity to PDE3A modulators.
- Further research is needed to develop PDE3A modulators for clinical application in myxoid LPS treatment.
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