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Multi-omic profiling of squamous cell lung cancer identifies metabolites and related genes associated with squamous cell carcinoma

Staaf, Johan LU orcid ; Ehinger, Daniel LU orcid ; Brunnström, Hans LU orcid ; Jönsson, Mats LU ; Rosengren, Frida LU ; Kotevska, Marija LU orcid ; Karlsson, Anna LU ; Aine, Mattias LU ; Frezza, Christian and Planck, Maria LU , et al. (2025) In Molecular Oncology
Abstract

Squamous cell lung carcinoma (SqCC) is the second most common histological subtype of lung cancer. Besides tumor-initiating and promoting DNA, RNA, and epigenetic alterations, aberrant cell metabolism is a hallmark of carcinogenesis. This study aimed to identify SqCC-specific key regulators that could eventually be used as new anticancer targets. Transcriptional and metabolomic data were gathered for a cohort of resected lung cancers. SqCC-specific differentially expressed genes were integrated with metabolic data. Findings were validated in cohorts of tumors, normal specimens, and cell lines. In situ protein expression of SLC6A8 was investigated. Differential gene expression analysis identified a subset of SqCC-specific genes with... (More)

Squamous cell lung carcinoma (SqCC) is the second most common histological subtype of lung cancer. Besides tumor-initiating and promoting DNA, RNA, and epigenetic alterations, aberrant cell metabolism is a hallmark of carcinogenesis. This study aimed to identify SqCC-specific key regulators that could eventually be used as new anticancer targets. Transcriptional and metabolomic data were gathered for a cohort of resected lung cancers. SqCC-specific differentially expressed genes were integrated with metabolic data. Findings were validated in cohorts of tumors, normal specimens, and cell lines. In situ protein expression of SLC6A8 was investigated. Differential gene expression analysis identified a subset of SqCC-specific genes with metabolic functions through the Reactome database, and/or correlated to specific metabolites through GEMs models. Metabolic profiling identified seven SqCC-specific metabolites, of which increased creatine levels, in particular, matched to SqCC-specific expression of SLC6A8. Expression of the gene appeared tumor cell-associated. Elevated creatine levels and overexpression of its transporter SLC6A8 appear a distinct metabolic feature of SqCC. Considering ongoing clinical trials in other malignancies, exploring SLC6A8 inhibition in SqCC appears motivated based on a metabolic addiction hypothesis.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
creatine, lung cancer, metabolomics, SLC6A8, squamous cell lung carcinoma
in
Molecular Oncology
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:40903981
  • scopus:105015506166
ISSN
1574-7891
DOI
10.1002/1878-0261.70121
language
English
LU publication?
yes
id
e81a0aac-3892-40c2-b283-024c5a9fd32b
date added to LUP
2025-11-13 14:18:22
date last changed
2025-11-27 15:37:00
@article{e81a0aac-3892-40c2-b283-024c5a9fd32b,
  abstract     = {{<p>Squamous cell lung carcinoma (SqCC) is the second most common histological subtype of lung cancer. Besides tumor-initiating and promoting DNA, RNA, and epigenetic alterations, aberrant cell metabolism is a hallmark of carcinogenesis. This study aimed to identify SqCC-specific key regulators that could eventually be used as new anticancer targets. Transcriptional and metabolomic data were gathered for a cohort of resected lung cancers. SqCC-specific differentially expressed genes were integrated with metabolic data. Findings were validated in cohorts of tumors, normal specimens, and cell lines. In situ protein expression of SLC6A8 was investigated. Differential gene expression analysis identified a subset of SqCC-specific genes with metabolic functions through the Reactome database, and/or correlated to specific metabolites through GEMs models. Metabolic profiling identified seven SqCC-specific metabolites, of which increased creatine levels, in particular, matched to SqCC-specific expression of SLC6A8. Expression of the gene appeared tumor cell-associated. Elevated creatine levels and overexpression of its transporter SLC6A8 appear a distinct metabolic feature of SqCC. Considering ongoing clinical trials in other malignancies, exploring SLC6A8 inhibition in SqCC appears motivated based on a metabolic addiction hypothesis.</p>}},
  author       = {{Staaf, Johan and Ehinger, Daniel and Brunnström, Hans and Jönsson, Mats and Rosengren, Frida and Kotevska, Marija and Karlsson, Anna and Aine, Mattias and Frezza, Christian and Planck, Maria and Arbajian, Elsa}},
  issn         = {{1574-7891}},
  keywords     = {{creatine; lung cancer; metabolomics; SLC6A8; squamous cell lung carcinoma}},
  language     = {{eng}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Molecular Oncology}},
  title        = {{Multi-omic profiling of squamous cell lung cancer identifies metabolites and related genes associated with squamous cell carcinoma}},
  url          = {{http://dx.doi.org/10.1002/1878-0261.70121}},
  doi          = {{10.1002/1878-0261.70121}},
  year         = {{2025}},
}