Proteomic Characterization of a Candidate Polygenic Driver of Metabolism in Non-small Cell Lung Cancer

Abstract

Proteome analysis revealed signatures of co-expressed upregulated metabolism proteins highly conserved between primary and non-small cell lung cancer (NSCLC) patient-derived xenograft tumors (Li et al. 2014, Nat. Communications 5:5469). The C10 signature is encoded by seven genes (ADSS, ATP2A2, CTPS1, IMPDH2, PKM2, PTGES3, SGPL1) and DNA alterations in C10-encoding genes are associated with longer survival in a subset of NSCLC. To explore the C10 signature as an oncogenic driver and address potential mechanisms of action, C10 protein expression and protein–protein interactions were determined. In independent NSCLC cohorts, the coordinated expression of C10 proteins was significant and mutations in C10 genes were associated with better outcome. Affinity purification-mass spectrometry and in vivo proximity-based biotin identification defined a C10 interactome involving 667 proteins including candidate drug targets and clusters associated with glycolysis, calcium homeostasis, and nucleotide and sphingolipid metabolism. DNA alterations in genes encoding C10 interactome components were also found to be associated with better survival. These data support the notion that the coordinated upregulation of the C10 signature impinges metabolic processes that collectively function as an oncogenic driver in NSCLC.