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

Hang Su, Li Chen, Jun Wu, Zhongyi Cheng, Jing Li, Yijiu Ren, Junfang Xu, Yifang Dang, Mengge Zheng, Yajuan Cao, Jiani Gao, Chenyang Dai, Xuefei Hu, Huikang Xie, Jianxia Chen, Tao Luo, Jun Zhu, Chunyan Wu (), Wei Sha (), Chang Chen () and Haipeng Liu ()
Additional contact information
Hang Su: Tongji University School of Medicine
Li Chen: Tongji University School of Medicine
Jun Wu: East China Normal University
Zhongyi Cheng: Jingjie PTM BioLab (Hangzhou). Co. Inc
Jing Li: Second Military Medical University
Yijiu Ren: Tongji University School of Medicine
Junfang Xu: Tongji University School of Medicine
Yifang Dang: Tongji University School of Medicine
Mengge Zheng: Tongji University School of Medicine
Yajuan Cao: Tongji University School of Medicine
Jiani Gao: Tongji University School of Medicine
Chenyang Dai: Tongji University School of Medicine
Xuefei Hu: Tongji University School of Medicine
Huikang Xie: Tongji University School of Medicine
Jianxia Chen: Tongji University School of Medicine
Tao Luo: Jingjie PTM BioLab (Hangzhou). Co. Inc
Jun Zhu: Jingjie PTM BioLab (Hangzhou). Co. Inc
Chunyan Wu: Tongji University School of Medicine
Wei Sha: Tongji University School of Medicine
Chang Chen: Tongji University School of Medicine
Haipeng Liu: Tongji University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57364-x

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