Abstract
ABSTRACTBackgroundSquamous 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 tumor cell metabolism has been identified as one of the hallmarks of carcinogenesis. The aim of the current study was to identify SqCC-specific metabolites and key gene regulators that could eventually be used as new anticancer targets.MethodsTranscriptional (n=156), proteomics (n=118), and mass spectrometry-based metabolomic data (n=73) were gathered for a cohort of resected early-stage lung cancers representing all major histological subgroups. SqCC-specific differentially expressed genes were integrated with proteogenomic and metabolic data using genome scale metabolic models (GEMs). Findings were validated in cohorts of tumors, normal specimens, and cancer cell lines. In situ protein expression of SLC6A8 was investigated in 213 tumors.ResultsDifferential gene expression analysis identified 280 SqCC-specific genes, of which 57 were connected to metabolites through GEMs. Metabolic profiling identified 7 SqCC-specific metabolites, of which increased creatine and decreased phosphocholine levels matched to SqCC-specific elevated expression ofSLC6A8and decreased expression ofCHKA,part of respective GEMs. Expression of both genes appeared tumor cell-associated, and in particular the elevated expression ofSLC6A8identified SqCC also in stage IV disease.ConclusionElevated creatine levels and the overexpression of its transporter protein SLC6A8 appear as a distinct metabolic feature of SqCC. Considering ongoing clinical trials focused on SLC6A8 inhibition in other malignancies, exploring SLC6A8 inhibition in SqCC appears motivated based on a metabolic addiction hypothesis.
Publisher
Cold Spring Harbor Laboratory