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

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.