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.
脂肪肉瘤是一组起源于脂肪组织的异质性恶性肿瘤。尽管脂肪肉瘤是最常见的软组织肉瘤亚型之一，但目前尚无精准医疗方案可用。为发现脂肪肉瘤亚型特异性治疗靶点，本研究对131例临床脂肪肉瘤组织样本进行RNA测序转录组分析，并将数据与包含95种健康组织和106种癌组织类型共20,218个样本的转录组数据库进行比对。通过Enrichr工具将鉴定出的基因与NCATS BioPlanet数据库进行通路富集分析，以研究上调信号通路。采用免疫组化检测181例脂肪肉瘤样本中PDE3A蛋白表达，通过RT-qPCR检测63例样本中PDE3A和SLFN12 mRNA表达。利用免疫印迹和细胞活力测定研究脂肪肉瘤细胞系及其对PDE3A调节剂的敏感性。研究结果显示：去分化型、黏液样型和多形性脂肪肉瘤亚型分别存在97、247和37个亚型特异性高表达基因。信号通路分析表明，去分化型脂肪肉瘤中刺猬信号通路高度激活，黏液样型中磷脂酶C介导级联反应和胰岛素信号通路活跃，多形性亚型则主要激活细胞增殖相关通路。研究发现PDE3A高表达与黏液样脂肪肉瘤（尤其是高级别肿瘤）存在显著关联。此外，黏液样脂肪肉瘤样本中SLFN12 mRNA表达水平升高。同时，共表达PDE3A和SLFN12的脂肪肉瘤细胞系SA4和GOT3对PDE3A调节剂表现敏感。本研究结果表明PDE3A调节剂是治疗黏液样脂肪肉瘤的潜在药物，后续需开展进一步研究以推动其临床应用。
PDE3AIs a Highly Expressed Therapy Target in Myxoid Liposarcoma
肿瘤(癌症)患者之家