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

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 LiYansheng Liu, Hui Zhang, Bing Zhang, Li Ding, Ana I. Robles, Henry Rodriguez, Daming Gao, Hongbin Ji, Hu Zhou, Peng Zhang

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

28 Scopus citations

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.

Original language	English
Pages (from-to)	184-203.e28
Journal	Cell
Volume	187
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2023.12.004
State	Published - Jan 4 2024

Keywords

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

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10.1016/j.cell.2023.12.004

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Liu, Q., Zhang, J., Guo, C., Wang, M., Wang, C., Yan, Y., Sun, L., Wang, D., Zhang, L., Yu, H., Hou, L., Wu, C., Zhu, Y., Jiang, G., Zhu, H., Zhou, Y., Fang, S., Zhang, T., Hu, L., ... Zhang, P. (2024). Proteogenomic characterization of small cell lung cancer identifies biological insights and subtype-specific therapeutic strategies. Cell, 187(1), 184-203.e28. https://doi.org/10.1016/j.cell.2023.12.004

@article{24b3fd356ec946908ce27376d051a35c,

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

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",

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

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2024",

month = jan,

day = "4",

doi = "10.1016/j.cell.2023.12.004",

language = "English",

volume = "187",

pages = "184--203.e28",

journal = "Cell",

issn = "0092-8674",

number = "1",

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Liu, Q, Zhang, J, Guo, C, Wang, M, Wang, C, Yan, Y, Sun, L, Wang, D, Zhang, L, Yu, H, Hou, L, Wu, C, Zhu, Y, Jiang, G, Zhu, H, Zhou, Y, Fang, S, Zhang, T, Hu, L, Li, J, Liu, Y, Zhang, H, Zhang, B, Ding, L, Robles, AI, Rodriguez, H, Gao, D, Ji, H, Zhou, H & Zhang, P 2024, 'Proteogenomic characterization of small cell lung cancer identifies biological insights and subtype-specific therapeutic strategies', Cell, vol. 187, no. 1, pp. 184-203.e28. https://doi.org/10.1016/j.cell.2023.12.004

TY - JOUR

T1 - Proteogenomic characterization of small cell lung cancer identifies biological insights and subtype-specific therapeutic strategies

AU - Liu, Qian

AU - Zhang, Jing

AU - Guo, Chenchen

AU - Wang, Mengcheng

AU - Wang, Chenfei

AU - Yan, Yilv

AU - Sun, Liangdong

AU - Wang, Di

AU - Zhang, Lele

AU - Yu, Huansha

AU - Hou, Likun

AU - Wu, Chunyan

AU - Zhu, Yuming

AU - Jiang, Gening

AU - Zhu, Hongwen

AU - Zhou, Yanting

AU - Fang, Shanhua

AU - Zhang, Tengfei

AU - Hu, Liang

AU - Li, Junqiang

AU - Liu, Yansheng

AU - Zhang, Hui

AU - Zhang, Bing

AU - Ding, Li

AU - Robles, Ana I.

AU - Rodriguez, Henry

AU - Gao, Daming

AU - Ji, Hongbin

AU - Zhou, Hu

AU - Zhang, Peng

PY - 2024/1/4

Y1 - 2024/1/4

N2 - 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.

AB - 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.

KW - HMGB3

KW - ZFHX3 mutation

KW - lung cancer

KW - mass spectrometry

KW - phosphoproteomics

KW - precision treatment

KW - proteogenomics

KW - proteomics

KW - small cell lung cancer

KW - tumor subtyping

UR - http://www.scopus.com/inward/record.url?scp=85181135968&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2023.12.004

DO - 10.1016/j.cell.2023.12.004

M3 - Article

C2 - 38181741

AN - SCOPUS:85181135968

SN - 0092-8674

VL - 187

SP - 184-203.e28

JO - Cell

JF - Cell

IS - 1

ER -

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

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Keywords

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