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

被引：55

作者：

Liu, Qian ^{[1
,2
]}

Zhang, Jing ^{[1
]}

Guo, Chenchen ^{[3
]}

Wang, Mengcheng ^{[3
,4
]}

Wang, Chenfei ^{[5
,6
]}

Yan, Yilv ^{[1
]}

Sun, Liangdong ^{[1
]}

Wang, Di ^{[1
]}

Zhang, Lele ^{[7
]}

Yu, Huansha ^{[1
]}

Hou, Likun ^{[8
]}

Wu, Chunyan ^{[8
]}

Zhu, Yuming ^{[1
]}

Jiang, Gening ^{[1
]}

Zhu, Hongwen

Zhou, Yanting ^{[2
]}

Fang, Shanhua ^{[2
]}

Zhang, Tengfei

Hu, Liang

Li, Junqiang ^{[9
]}

Liu, Yansheng ^{[10
]}

Zhang, Hui ^{[11
]}

Zhang, Bing ^{[12
]}

Ding, Li ^{[13
]}

Robles, Ana I. ^{[14
]}

Rodriguez, Henry ^{[14
]}

Gao, Daming ^{[3
,4
,15
]}

Ji, Hongbin ^{[3
,4
,15
,17
]}

Zhou, Hu ^{[2
,4
,16
]}

Zhang, Peng ^{[1
]}

机构：

[1] Tongji Univ, Shanghai Pulm Hosp, Sch Med, Dept Thorac Surg, Shanghai 200433, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Analyt Chem, Shanghai 201203, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci, State Key Lab Cell Biol, Shanghai 200031, Peoples R China

[4] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[5] Tongji Univ, Tongji Hosp, Sch Life Sci & Technol, Dept Orthoped,Key Lab Spine & Spinal Cord Injury R, Shanghai 200092, Peoples R China

[6] Tongji Univ, Frontier Sci Ctr Stem Cells, Sch Life Sci & Technol, Shanghai 200092, Peoples R China

[7] Tongji Univ, Shanghai Pulm Hosp, Sch Med, Cent Lab, Shanghai 200433, Peoples R China

[8] Tongji Univ, Shanghai Pulm Hosp, Sch Med, Dept Pathol, Shanghai 200433, Peoples R China

[9] D1 Med Technol, Shanghai 201800, Peoples R China

[10] Yale Univ, Sch Med, Canc Biol Inst, West Haven, CT 06516 USA

[11] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA

[12] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA

[13] Washington Univ, McDonnell Genome Inst, Dept Med, St Louis, MO 63108 USA

[14] NCI, Off Canc Clin Prote Res, NIH, Rockville, MD 20850 USA

[15] Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Key Lab Syst Hlth Sci Zhejiang Prov, Hangzhou 310024, Peoples R China

[16] Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China

[17] Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200120, Peoples R China

来源：

CELL | 2024年 / 187卷 / 01期

基金：

中国博士后科学基金; 中国国家自然科学基金;

关键词：

TO-MESENCHYMAL TRANSITION; DNA-DAMAGE REPAIR; MOLECULAR SIGNATURES; GENOMIC ANALYSIS; READ ALIGNMENT; POOR-PROGNOSIS; AURORA KINASE; MUTATIONS; GENE; PROLIFERATION;

D O I：

10.1016/j.cell.2023.12.004

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We performed comprehensive proteogenomic characterization of small cell lung cancer (SCLC) using paired tumors and adjacent lung tissues from 112 treatmentnaive 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.

引用

页码：184 / 203.e28

页数：49

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