Publication Date
1-1-2023
Journal
Cancer Medicine
DOI
10.1002/cam4.4933
PMID
35676822
PMCID
PMC9844651
PubMedCentral® Posted Date
6-8-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Humans, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Transcriptome, Adenocarcinoma of Lung, Gene Expression Profiling, adenocarcinoma of lung; carcinoma, non‐small‐cell lung; carcinoma, squamous cell; drug repositioning; lung neoplasms; metabolomics; systems biology; transcriptome
Abstract
BACKGROUND: Non-small cell lung cancer (NSCLC) comprises the majority (~85%) of all lung tumors, with lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) being the most frequently diagnosed histological subtypes. Multi-modal omics profiling has been carried out in NSCLC, but no studies have yet reported a unique metabolite-related gene signature and altered metabolic pathways associated with LUAD and LUSC.
METHODS: We integrated transcriptomics and metabolomics to analyze 30 human lung tumors and adjacent noncancerous tissues. Differential co-expression was used to identify modules of metabolites that were altered between normal and tumor.
RESULTS: We identified unique metabolite-related gene signatures specific for LUAD and LUSC and key pathways aberrantly regulated at both transcriptional and metabolic levels. Differential co-expression analysis revealed that loss of coherence between metabolites in tumors is a major characteristic in both LUAD and LUSC. We identified one metabolic onco-module gained in LUAD, characterized by nine metabolites and 57 metabolic genes. Multi-omics integrative analysis revealed a 28 metabolic gene signature associated with poor survival in LUAD, with six metabolite-related genes as individual prognostic markers.
CONCLUSIONS: We demonstrated the clinical utility of this integrated metabolic gene signature in LUAD by using it to guide repurposing of AZD-6482, a PI3Kβ inhibitor which significantly inhibited three genes from the 28-gene signature. Overall, we have integrated metabolomics and transcriptomics analyses to show that LUAD and LUSC have distinct profiles, inferred gene signatures with prognostic value for patient survival, and identified therapeutic targets and repurposed drugs for potential use in NSCLC treatment.
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Biological Phenomena, Cell Phenomena, and Immunity Commons, Life Sciences Commons, Medical Cell Biology Commons, Medical Microbiology Commons, Medical Molecular Biology Commons, Neoplasms Commons, Oncology Commons, Pulmonology Commons, Respiratory Tract Diseases Commons
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