文章：

PIK3CA突变强化了血管癌中免疫信号的分子决定因素

PIK3CA mutation fortifies molecular determinants for immune signaling in vascular cancers 

原文发布日期：2024-12-21 

英文摘要：

Angiosarcomas are a group of vascular cancers that form malignant blood vessels. These malignancies are seemingly inflamed primarily due to their pathognomonic nature, which consists of irregular endothelium and tortuous blood channels. PIK3CA mutations are oncogenic and disrupt the PI3K pathway. In this study, we aimed to define the molecular and functional consequences of oncogenic PIK3CA mutations in angiosarcoma. We first generated two isogenic hemangiosarcoma cell lines harboring the H1047R hotspot mutations in PIK3CA gene using CRISPR/Cas9. We found PIK3CA-mutant cells established distinct molecular signatures in global gene expression and chromatin accessibility, which were associated with enrichment of immune cytokine signaling, including IL-6, IL-8, and MCP-1. These molecular processes were disrupted by the PI3K-α specific inhibitor, alpelisib. We also observed that the molecular distinctions in PIK3CA-mutant cells were linked to metabolic reprogramming in glycolytic activity and mitochondrial respiration. Our multi-omics analysis revealed that activating PIK3CA mutations regulate molecular machinery that contributes to phenotypic alterations and resistance to alpelisib. Furthermore, we identified potential therapeutic vulnerabilities of PIK3CA mutations in response to PI3K-α inhibition mediated by MAPK signaling. In summary, we demonstrate that PIK3CA mutations perpetuate PI3K activation and reinforce immune enrichment to promote drug resistance in vascular cancers.

摘要翻译：

血管肉瘤是一组形成恶性血管的血管癌症。这些恶性肿瘤看似发炎主要源于其病征性质，即由不规则内皮和迂曲血管通道构成。PIK3CA突变具有致癌性，会破坏PI3K通路。本研究旨在阐明致癌性PIK3CA突变在血管肉瘤中的分子和功能影响。我们首先利用CRISPR/Cas9技术构建了两种携带PIK3CA基因H1047R热点突变的同源遗传性血管肉瘤细胞系。发现PIK3CA突变细胞在全局基因表达和染色质可及性方面建立了独特的分子特征，这些特征与免疫细胞因子信号（包括IL-6、IL-8和MCP-1）的富集相关。这些分子过程可被PI3K-α特异性抑制剂阿培利司破坏。我们还观察到PIK3CA突变细胞的分子差异与糖酵解活性和线粒体呼吸中的代谢重编程相关。多组学分析表明，激活的PIK3CA突变调控了导致表型改变和阿培利司耐药的分子机制。此外，我们发现了PIK3CA突变通过MAPK信号通路响应PI3K-α抑制后的潜在治疗脆弱性。综上，我们证明PIK3CA突变使PI3K持续激活并增强免疫富集，从而促进血管癌症的耐药性。

原文链接：

PIK3CA mutation fortifies molecular determinants for immune signaling in vascular cancers