Proteogenomic characterization of small cell lung cancer identifies biological insights and subtype-specific therapeutic strategies

IF 42.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2024-01-04 DOI:10.1016/j.cell.2023.12.004

Qian Liu, Jing Zhang, Chenchen Guo, Mengcheng Wang, Chenfei Wang, Yilv Yan, Liangdong Sun, Di Wang, Lele Zhang, Huansha Yu, Likun Hou, Chunyan Wu, Yuming Zhu, Gening Jiang, Hongwen Zhu, Yanting Zhou, Shanhua Fang, Tengfei Zhang, Liang Hu, Junqiang Li, Peng Zhang

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Abstract

We performed comprehensive proteogenomic characterization of small cell lung cancer (SCLC) using paired tumors and adjacent lung tissues from 112 treatment-naive patients who underwent surgical resection. Integrated multi-omics analysis illustrated cancer biology downstream of genetic aberrations and highlighted oncogenic roles of FAT1 mutation, RB1 deletion, and chromosome 5q loss. Two prognostic biomarkers, HMGB3 and CASP10, were identified. Overexpression of HMGB3 promoted SCLC cell migration via transcriptional regulation of cell junction-related genes. Immune landscape characterization revealed an association between ZFHX3 mutation and high immune infiltration and underscored a potential immunosuppressive role of elevated DNA damage response activity via inhibition of the cGAS-STING pathway. Multi-omics clustering identified four subtypes with subtype-specific therapeutic vulnerabilities. Cell line and patient-derived xenograft-based drug tests validated the specific therapeutic responses predicted by multi-omics subtyping. This study provides a valuable resource as well as insights to better understand SCLC biology and improve clinical practice.

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小细胞肺癌的蛋白质基因组特征鉴定生物学见解和亚型特异性治疗策略

我们利用112名接受手术切除的未经治疗患者的配对肿瘤和邻近肺组织，对小细胞肺癌（SCLC）进行了全面的蛋白质基因组学鉴定。综合多组学分析显示了基因畸变下游的癌症生物学特性，并突出了FAT1突变、RB1缺失和5q染色体缺失的致癌作用。研究发现了两个预后生物标志物--HMGB3和CASP10。HMGB3的过表达通过细胞连接相关基因的转录调控促进了SCLC细胞的迁移。免疫图谱表征揭示了ZFHX3突变与高免疫浸润之间的关联，并强调了DNA损伤应答活性升高通过抑制cGAS-STING通路可能起到的免疫抑制作用。多组学聚类分析确定了具有亚型特异性治疗脆弱性的四种亚型。基于细胞系和患者来源异种移植的药物试验验证了多组学亚型预测的特异性治疗反应。这项研究为更好地了解SCLC生物学和改善临床实践提供了宝贵的资源和见解。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.