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

Heba Badr; Ron Blutrich; Kaitlin Chan; Jiefei Tong; Paul Taylor; Wen Zhang; Ran Kafri; Hannes L Röst; Ming-Sound Tsao; Michael F Moran

doi:10.1016/j.jmb.2022.167636

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

J Mol Biol. 2022 Jul 15;434(13):167636. doi: 10.1016/j.jmb.2022.167636. Epub 2022 May 18.

Authors

Affiliations

¹ Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
² Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada.
³ Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; SPARC BioCentre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁴ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁵ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Departments of Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada.
⁶ Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada; SPARC BioCentre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada. Electronic address: mmoran@sickkids.ca.

PMID: 35595168
DOI: 10.1016/j.jmb.2022.167636

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.

Keywords: LC-MS/MS; NSCLC; interactome; metabolism; proteomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Non-Small-Cell Lung* / genetics
DNA
Humans
Lung Neoplasms* / metabolism
Proteome / metabolism
Proteomics / methods

Substances

Proteome
DNA