蛋白质基因组学特征揭示了以亚实性结节表现的肺癌的肿瘤发生和进展。

Proteogenomic characterization reveals tumorigenesis and progression of lung cancer manifested as subsolid nodules.

作者信息

Su Hang, Chen Li, Wu Jun, Cheng Zhongyi, Li Jing, Ren Yijiu, Xu Junfang, Dang Yifang, Zheng Mengge, Cao Yajuan, Gao Jiani, Dai Chenyang, Hu Xuefei, Xie Huikang, Chen Jianxia, Luo Tao, Zhu Jun, Wu Chunyan, Sha Wei, Chen Chang, Liu Haipeng

机构信息

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

Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.

出版信息

Nat Commun. 2025 Mar 11;16(1):2414. doi: 10.1038/s41467-025-57364-x.

DOI:10.1038/s41467-025-57364-x

PMID:40069142

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11897189/

Abstract

Lung adenocarcinoma (LUAD) radiologically displayed as subsolid nodules (SSNs) is prevalent. Nevertheless, the precise clinical management of SSNs necessitates a profound understanding of their tumorigenesis and progression. Here, we analyze 66 LUAD displayed as SSNs covering 3 histological stages including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) by incorporating genomics, proteomics, phosphoproteomics and glycoproteomics. Intriguingly, cholesterol metabolism is aberrantly regulated in the preneoplastic AIS stage. Importantly, target ablation of proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the initiation of LUAD. Furthermore, sustained endoplasmic reticulum stress is demonstrated to be a hallmark and a reliable biomarker of AIS progression to IAC. Consistently, target promotion of ER stress profoundly retards LUAD progression. Our study provides comprehensive proteogenomic landscape of SSNs, sheds lights on the tumorigenesis and progression of SSNs and suggests preventive and therapeutic strategies for LUAD.

摘要

在放射学上表现为亚实性结节（SSN）的肺腺癌（LUAD）很常见。然而，对SSN进行精确的临床管理需要深入了解其肿瘤发生和进展情况。在此，我们通过整合基因组学、蛋白质组学、磷酸化蛋白质组学和糖蛋白质组学，分析了66例表现为SSN的LUAD，涵盖3个组织学阶段，包括原位腺癌（AIS）、微浸润腺癌（MIA）和浸润性腺癌（IAC）。有趣的是，在肿瘤前的AIS阶段，胆固醇代谢受到异常调节。重要的是，前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）的靶向消融促进了LUAD的发生。此外，持续的内质网应激被证明是AIS进展为IAC的一个标志和可靠的生物标志物。一致地，内质网应激的靶向促进显著延缓了LUAD的进展。我们的研究提供了SSN的全面蛋白质基因组图谱，阐明了SSN的肿瘤发生和进展，并提出了LUAD的预防和治疗策略。