Integration of Pan-Cancer Transcriptomics With RPPA Proteomics Reveals Mechanisms of Epithelial-Mesenchymal Transition

PLoS Comput Biol. 2018 Jan 2;14(1):e1005911. doi: 10.1371/journal.pcbi.1005911. eCollection 2018 Jan.

Abstract

Integrating data from multiple regulatory layers across cancer types could elucidate additional mechanisms of oncogenesis. Using antibody-based protein profiling of 736 cancer cell lines, along with matching transcriptomic data, we show that pan-cancer bimodality in the amounts of mRNA, protein, and protein phosphorylation reveals mechanisms related to the epithelial-mesenchymal transition (EMT). Based on the bimodal expression of E-cadherin, we define an EMT signature consisting of 239 genes, many of which were not previously associated with EMT. By querying gene expression signatures collected from cancer cell lines after small-molecule perturbations, we identify enrichment for histone deacetylase (HDAC) inhibitors as inducers of EMT, and kinase inhibitors as mesenchymal-to-epithelial transition (MET) promoters. Causal modeling of protein-based signaling identifies putative drivers of EMT. In conclusion, integrative analysis of pan-cancer proteomic and transcriptomic data reveals key regulatory mechanisms of oncogenic transformation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigens, CD
  • Cadherins / genetics
  • Cadherins / metabolism
  • Carcinogenesis
  • Cell Line, Tumor
  • Computational Biology
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics*
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Models, Genetic
  • Models, Statistical
  • Neoplasms / genetics*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Phosphorylation
  • Protein Array Analysis / statistics & numerical data
  • Protein Kinase Inhibitors / pharmacology
  • Proteomics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Transcriptome

Substances

  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • Histone Deacetylase Inhibitors
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • RNA, Neoplasm