小细胞肺癌的蛋白质基因组学特征分析为其提供了生物学见解和亚型特异性的治疗策略。

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

机构信息

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China; Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China.

出版信息

Cell. 2024 Jan 4;187(1):184-203.e28. doi: 10.1016/j.cell.2023.12.004.

DOI:10.1016/j.cell.2023.12.004

PMID:38181741

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.

摘要

我们对 112 名未经治疗的接受手术切除的小细胞肺癌 (SCLC) 患者的配对肿瘤和相邻肺组织进行了全面的蛋白质基因组学特征分析。综合多组学分析说明了遗传异常下游的癌症生物学，并强调了 FAT1 突变、RB1 缺失和 5q 染色体缺失的致癌作用。鉴定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 SCLC 细胞迁移。免疫景观特征表明 ZFHX3 突变与高免疫浸润之间存在关联，并通过抑制 cGAS-STING 通路抑制 DNA 损伤反应活性，强调了其潜在的免疫抑制作用。多组学聚类确定了具有特定治疗弱点的四个亚型。基于细胞系和患者来源的异种移植的药物测试验证了多组学亚型预测的特定治疗反应。这项研究提供了有价值的资源以及对更好地理解 SCLC 生物学和改善临床实践的深入了解。