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.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.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).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.
