整合多组学揭示肺腺癌中合成致死相关特征的预后和治疗图谱
Integrative multi-omics reveals a prognostic and therapeutic landscape of synthetic lethality-associated signatures in lung adenocarcinoma.
作者
作者单位
- Department of Pharmacy, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China.
- Department of Pharmacy, The Third People's Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, P.R. China.
- Clinical Research Center, Medical Pathology Center, Cancer Early Detection, and Treatment Center and Translational Medicine Research Center, Chongqing University Three Gorges Hospital, Chongqing University, Chongqing, P.R. China.
摘要
中文
肺腺癌（LUAD）表现出相当大的异质性和治疗耐药性。在这里，我们整合了单细胞RNA测序、空间转录组学和机器学习来表征LUAD中合成致死（SL）相关的转录活性。我们在恶性上皮细胞中量化了SL活性，并将其分为高SL、主导SL和低SL组。高SL细胞在晚期和转移性样本中富集，并显示出降低的分化潜力。通过多种机器学习算法，我们确定了13个高SL特征基因，其中IFRD2（干扰素相关发育调节因子2）是主要贡献者之一。实验验证证实了IFRD2在高恶性细胞系中上调，IFRD2敲低调节了对PARP抑制剂niraparib的敏感性。预测的化合物前列腺素A1对LUAD细胞表现出选择性细胞毒性，并诱导DNA损伤，与SL相关机制一致。我们的发现建立了一个识别SL相关脆弱性的框架，并为LUAD精准治疗中的进一步机制研究提供了候选基因和化合物资源。
English
Lung adenocarcinoma (LUAD) exhibits considerable heterogeneity and therapeutic resistance. Here, we integrated single-cell RNA sequencing, spatial transcriptomics, and machine learning to characterize synthetic lethality (SL)-associated transcriptional activity in LUAD. We quantified SL activity across malignant epithelial cells and stratified them into high-, dominant-, and low-SL groups. High-SL cells were enriched in advanced-stage and metastatic samples and showed reduced differentiation potential. Through multiple machine learning algorithms, we identified 13 high-SL signature genes, with IFRD2 (interferon-related developmental regulator 2) among the top contributors. Experimental validation confirmed IFRD2 upregulation in high-malignancy cell lines, and IFRD2 knockdown modulated sensitivity to the PARP inhibitor niraparib. The predicted compound prostaglandin A1 exhibited selective cytotoxicity against LUAD cells and induced DNA damage, consistent with an SL-related mechanism. Our findings establish a framework for identifying SL-associated vulnerabilities and provide a resource of candidate genes and compounds for further mechanistic investigation in LUAD precision therapy.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 4.5
- 新锐分区
- 3区