Proteogenomic characterization reveals tumorigenesis and progression of lung cancer manifested as subsolid nodules
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.
Authors
- Huikang Xie (ORCID: https://orcid.org/0000-0002-6007-3418)
- Tao Luo (ORCID: https://orcid.org/0000-0002-7706-5131)
- Yajuan Cao (ORCID: https://orcid.org/0000-0001-8685-5787)
- Yijiu Ren
- Jiani Gao (ORCID: https://orcid.org/0000-0003-1422-8180)
- Zhongyi Cheng (ORCID: https://orcid.org/0000-0002-8764-2019)
- Junfang Xu (ORCID: https://orcid.org/0000-0001-9133-8960)
- Mengge Zheng
- Yifang Dang
- Jing Li (ORCID: https://orcid.org/0000-0002-7973-3930)
- Chang Chen (ORCID: https://orcid.org/0000-0003-2841-1250)
- Haipeng Liu (ORCID: https://orcid.org/0000-0002-3338-6291)
- Wei Sha (ORCID: https://orcid.org/0000-0002-2099-8205)
- Lixia Chen (ORCID: https://orcid.org/0000-0003-2196-1428)
- Jun Wu (ORCID: https://orcid.org/0000-0003-2798-070X)
- Chunyan Wu (ORCID: https://orcid.org/0000-0003-3771-4886)
- Chenyang Dai (ORCID: https://orcid.org/0000-0001-9609-0343)
- Jianxia Chen (ORCID: https://orcid.org/0009-0000-7548-7261)
- Jun Zhu
- Hang Su (ORCID: https://orcid.org/0000-0003-0571-0864)
- Xuefei Hu (ORCID: https://orcid.org/0000-0003-1873-9500)
Institutions
- Tongji University (CN)
- Second Military Medical University (CN)
- Changhai Hospital (CN)
- Shanghai Pulmonary Hospital (CN)
- New England Biolabs (China) (CN)
- East China Normal University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-11
- DOI
- https://doi.org/10.1038/s41467-025-57364-x
- Citations
- 7
- Primary Topic
- Genomics and Phylogenetic Studies
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- National Natural Science Foundation of China