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

Qian Liu; Jing Zhang; Chenchen Guo; Mengcheng Wang; Chenfei Wang; Yilv Yan; Liangdong Sun; Di Wang; Lele Zhang; Huansha Yu; Likun Hou; Chunyan Wu; Yuming Zhu; Gening Jiang; Hongwen Zhu; Yanting Zhou; Shanhua Fang; Tengfei Zhang; Liang Hu; Junqiang Li; Yansheng Liu; Hui Zhang; Bing Zhang; Li Ding; Ana I Robles; Henry Rodriguez; Daming Gao; Hongbin Ji; Hu Zhou; Peng Zhang

doi:10.1016/j.cell.2023.12.004

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

Cell. 2024 Jan 4;187(1):184-203.e28. doi: 10.1016/j.cell.2023.12.004.

Authors

Qian Liu¹, Jing Zhang², Chenchen Guo³, Mengcheng Wang⁴, Chenfei Wang⁵, Yilv Yan², Liangdong Sun², Di Wang², Lele Zhang⁶, Huansha Yu², Likun Hou⁷, Chunyan Wu⁷, Yuming Zhu², Gening Jiang², Hongwen Zhu⁸, Yanting Zhou⁸, Shanhua Fang⁸, Tengfei Zhang⁴, Liang Hu³, Junqiang Li⁹, Yansheng Liu¹⁰, Hui Zhang¹¹, Bing Zhang¹², Li Ding¹³, Ana I Robles¹⁴, Henry Rodriguez¹⁴, Daming Gao¹⁵, Hongbin Ji¹⁶, Hu Zhou¹⁷, Peng Zhang¹⁸

Affiliations

¹ Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China; Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China.
³ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
⁴ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁵ Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Frontier Science Center for Stem Cells, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
⁶ Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China.
⁷ Department of Pathology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China.
⁸ Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁹ D1 Medical Technology, Shanghai 201800, China.
¹⁰ Cancer Biology Institute, Yale University School of Medicine, West Haven, CT 06516, USA.
¹¹ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹² Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹³ Department of Medicine, McDonnell Genome Institute, Washington University, St. Louis, MO 63108, USA.
¹⁴ Office of Cancer Clinical Proteomics Research, National Cancer Institute, National Institutes of Health, Rockville, MD 20850, USA.
¹⁵ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: dgao@sibcb.ac.cn.
¹⁶ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China. Electronic address: hbji@sibcb.ac.cn.
¹⁷ Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: zhouhu@simm.ac.cn.
¹⁸ Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China. Electronic address: zhangpeng1121@tongji.edu.cn.

PMID: 38181741
DOI: 10.1016/j.cell.2023.12.004

Abstract

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

Keywords: HMGB3; ZFHX3 mutation; lung cancer; mass spectrometry; phosphoproteomics; precision treatment; proteogenomics; proteomics; small cell lung cancer; tumor subtyping.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / analysis
Cell Line
Heterografts
Humans
Lung Neoplasms* / chemistry
Lung Neoplasms* / genetics
Proteogenomics*
Small Cell Lung Carcinoma* / chemistry
Small Cell Lung Carcinoma* / genetics

Substances

Biomarkers, Tumor