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; Haipeng Liu

doi:10.1038/s41467-025-57364-x

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^*

Haipeng Liu^*

^*Corresponding author for this work

School of Life Sciences

Tongji University
Jingjie PTM BioLab (Hangzhou). Co. Inc
Second Military Medical University

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	English
Article number	2414
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-57364-x
State	Published - Dec 2025

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SDG 3 Good Health and Well-being

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Su, H., Chen, L., Wu, J., Cheng, Z., Li, J., Ren, Y., Xu, J., Dang, Y., Zheng, M., Cao, Y., Gao, J., Dai, C., Hu, X., Xie, H., Chen, J., Luo, T., Zhu, J., Wu, C., Sha, W., ... Liu, H. (2025). Proteogenomic characterization reveals tumorigenesis and progression of lung cancer manifested as subsolid nodules. Nature Communications, 16(1), Article 2414. https://doi.org/10.1038/s41467-025-57364-x

@article{71c80b2cbd32474cac1031125ea1b854,

title = "Proteogenomic characterization reveals tumorigenesis and progression of lung cancer manifested as subsolid nodules",

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.",

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

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41467-025-57364-x",

language = "英语",

volume = "16",

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Su, H, Chen, L, Wu, J, Cheng, Z, Li, J, Ren, Y, Xu, J, Dang, Y, Zheng, M, Cao, Y, Gao, J, Dai, C, Hu, X, Xie, H, Chen, J, Luo, T, Zhu, J, Wu, C, Sha, W, Chen, C & Liu, H 2025, 'Proteogenomic characterization reveals tumorigenesis and progression of lung cancer manifested as subsolid nodules', Nature Communications, vol. 16, no. 1, 2414. https://doi.org/10.1038/s41467-025-57364-x

TY - JOUR

T1 - Proteogenomic characterization reveals tumorigenesis and progression of lung cancer manifested as subsolid nodules

AU - Su, Hang

AU - Chen, Li

AU - Wu, Jun

AU - Cheng, Zhongyi

AU - Li, Jing

AU - Ren, Yijiu

AU - Xu, Junfang

AU - Dang, Yifang

AU - Zheng, Mengge

AU - Cao, Yajuan

AU - Gao, Jiani

AU - Dai, Chenyang

AU - Hu, Xuefei

AU - Xie, Huikang

AU - Chen, Jianxia

AU - Luo, Tao

AU - Zhu, Jun

AU - Wu, Chunyan

AU - Sha, Wei

AU - Chen, Chang

AU - Liu, Haipeng

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105000059666

U2 - 10.1038/s41467-025-57364-x

DO - 10.1038/s41467-025-57364-x

M3 - 文章

C2 - 40069142

AN - SCOPUS:105000059666

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2414

ER -

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

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