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In-depth proteomic analysis reveals unique subtype-specific signatures in human small-cell lung cancer

Szeitz, Beáta ; Megyesfalvi, Zsolt ; Woldmar, Nicole LU ; Valkó, Zsuzsanna ; Schwendenwein, Anna ; Bárány, Nándor ; Paku, Sándor ; László, Viktória ; Kiss, Helga and Bugyik, Edina , et al. (2022) In Clinical and Translational Medicine 12(9). p.1060-1060
Abstract

BACKGROUND: Small-cell lung cancer (SCLC) molecular subtypes have been primarily characterized based on the expression pattern of the following key transcription regulators: ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P) and YAP1 (SCLC-Y). Here, we investigated the proteomic landscape of these molecular subsets with the aim to identify novel subtype-specific proteins of diagnostic and therapeutic relevance.

METHODS: Pellets and cell media of 26 human SCLC cell lines were subjected to label-free shotgun proteomics for large-scale protein identification and quantitation, followed by in-depth bioinformatic analyses. Proteomic data were correlated with the cell lines' phenotypic characteristics and with public transcriptomic data... (More)

BACKGROUND: Small-cell lung cancer (SCLC) molecular subtypes have been primarily characterized based on the expression pattern of the following key transcription regulators: ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P) and YAP1 (SCLC-Y). Here, we investigated the proteomic landscape of these molecular subsets with the aim to identify novel subtype-specific proteins of diagnostic and therapeutic relevance.

METHODS: Pellets and cell media of 26 human SCLC cell lines were subjected to label-free shotgun proteomics for large-scale protein identification and quantitation, followed by in-depth bioinformatic analyses. Proteomic data were correlated with the cell lines' phenotypic characteristics and with public transcriptomic data of SCLC cell lines and tissues.

RESULTS: Our quantitative proteomic data highlighted that four molecular subtypes are clearly distinguishable at the protein level. The cell lines exhibited diverse neuroendocrine and epithelial-mesenchymal characteristics that varied by subtype. A total of 367 proteins were identified in the cell pellet and 34 in the culture media that showed significant up- or downregulation in one subtype, including known druggable proteins and potential blood-based markers. Pathway enrichment analysis and parallel investigation of transcriptomics from SCLC cell lines outlined unique signatures for each subtype, such as upregulated oxidative phosphorylation in SCLC-A, DNA replication in SCLC-N, neurotrophin signalling in SCLC-P and epithelial-mesenchymal transition in SCLC-Y. Importantly, we identified the YAP1-driven subtype as the most distinct SCLC subgroup. Using sparse partial least squares discriminant analysis, we identified proteins that clearly distinguish four SCLC subtypes based on their expression pattern, including potential diagnostic markers for SCLC-Y (e.g. GPX8, PKD2 and UFO).

CONCLUSIONS: We report for the first time, the protein expression differences among SCLC subtypes. By shedding light on potential subtype-specific therapeutic vulnerabilities and diagnostic biomarkers, our results may contribute to a better understanding of SCLC biology and the development of novel therapies.

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type
Contribution to journal
publication status
published
subject
keywords
Biomarkers, Cell Line, Tumor, Culture Media, Gene Expression Regulation, Neoplastic/genetics, Humans, Lung Neoplasms/drug therapy, Nerve Growth Factors/genetics, Peroxidases/genetics, Proteomics, Small Cell Lung Carcinoma/genetics
in
Clinical and Translational Medicine
volume
12
issue
9
pages
1060 - 1060
publisher
Wiley
external identifiers
  • pmid:36149789
ISSN
2001-1326
DOI
10.1002/ctm2.1060
language
English
LU publication?
yes
additional info
© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
id
207dd725-a27c-4d81-b5af-006c2e056359
date added to LUP
2023-11-30 13:24:25
date last changed
2023-12-13 14:23:53
@article{207dd725-a27c-4d81-b5af-006c2e056359,
  abstract     = {{<p>BACKGROUND: Small-cell lung cancer (SCLC) molecular subtypes have been primarily characterized based on the expression pattern of the following key transcription regulators: ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P) and YAP1 (SCLC-Y). Here, we investigated the proteomic landscape of these molecular subsets with the aim to identify novel subtype-specific proteins of diagnostic and therapeutic relevance.</p><p>METHODS: Pellets and cell media of 26 human SCLC cell lines were subjected to label-free shotgun proteomics for large-scale protein identification and quantitation, followed by in-depth bioinformatic analyses. Proteomic data were correlated with the cell lines' phenotypic characteristics and with public transcriptomic data of SCLC cell lines and tissues.</p><p>RESULTS: Our quantitative proteomic data highlighted that four molecular subtypes are clearly distinguishable at the protein level. The cell lines exhibited diverse neuroendocrine and epithelial-mesenchymal characteristics that varied by subtype. A total of 367 proteins were identified in the cell pellet and 34 in the culture media that showed significant up- or downregulation in one subtype, including known druggable proteins and potential blood-based markers. Pathway enrichment analysis and parallel investigation of transcriptomics from SCLC cell lines outlined unique signatures for each subtype, such as upregulated oxidative phosphorylation in SCLC-A, DNA replication in SCLC-N, neurotrophin signalling in SCLC-P and epithelial-mesenchymal transition in SCLC-Y. Importantly, we identified the YAP1-driven subtype as the most distinct SCLC subgroup. Using sparse partial least squares discriminant analysis, we identified proteins that clearly distinguish four SCLC subtypes based on their expression pattern, including potential diagnostic markers for SCLC-Y (e.g. GPX8, PKD2 and UFO).</p><p>CONCLUSIONS: We report for the first time, the protein expression differences among SCLC subtypes. By shedding light on potential subtype-specific therapeutic vulnerabilities and diagnostic biomarkers, our results may contribute to a better understanding of SCLC biology and the development of novel therapies.</p>}},
  author       = {{Szeitz, Beáta and Megyesfalvi, Zsolt and Woldmar, Nicole and Valkó, Zsuzsanna and Schwendenwein, Anna and Bárány, Nándor and Paku, Sándor and László, Viktória and Kiss, Helga and Bugyik, Edina and Lang, Christian and Szász, Attila Marcell and Pizzatti, Luciana and Bogos, Krisztina and Hoda, Mir Alireza and Hoetzenecker, Konrad and Marko-Varga, György and Horvatovich, Peter and Döme, Balázs and Schelch, Karin and Rezeli, Melinda}},
  issn         = {{2001-1326}},
  keywords     = {{Biomarkers; Cell Line, Tumor; Culture Media; Gene Expression Regulation, Neoplastic/genetics; Humans; Lung Neoplasms/drug therapy; Nerve Growth Factors/genetics; Peroxidases/genetics; Proteomics; Small Cell Lung Carcinoma/genetics}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{1060--1060}},
  publisher    = {{Wiley}},
  series       = {{Clinical and Translational Medicine}},
  title        = {{In-depth proteomic analysis reveals unique subtype-specific signatures in human small-cell lung cancer}},
  url          = {{http://dx.doi.org/10.1002/ctm2.1060}},
  doi          = {{10.1002/ctm2.1060}},
  volume       = {{12}},
  year         = {{2022}},
}