Systems analysis of the NCI-60 cancer cell lines by alignment of protein pathway activation modules with "-OMIC" data fields and therapeutic response signatures

Giulia Federici, Xi Gao, Janusz Slawek, Tomasz Arodz, Amanuel Shitaye, Julia D. Wulfkuhle, Ruggero De Maria, Lance A. Liotta, Emanuel F. Petricoin

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The NCI-60 cell line set is likely the most molecularly profiled set of human tumor cell lines in the world. However, a critical missing component of previous analyses has been the inability to place the massive amounts of "-omic" data in the context of functional protein signaling networks, which often contain many of the drug targets for new targeted therapeutics. We used reverse-phase protein array (RPPA) analysis to measure the activation/phosphorylation state of 135 proteins, with a total analysis of nearly 200 key protein isoforms involved in cell proliferation, survival, migration, adhesion, etc., in all 60 cell lines. We aggregated the signaling data into biochemical modules of interconnected kinase substrates for 6 key cancer signaling pathways: AKT, mTOR, EGF receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), integrin, and apoptosis signaling. The net activation state of these protein network modules was correlated to available individual protein, phosphoprotein, mutational, metabolomic, miRNA, transcriptional, and drug sensitivity data. Pathway activation mapping identified reproducible and distinct signaling cohorts that transcended organ-type distinctions. Direct correlations with the protein network modules involved largely protein phosphorylation data but we also identified direct correlations of signaling networks with metabolites, miRNA, and DNA data. The integration of protein activation measurements into biochemically interconnected modules provided a novel means to align the functional protein architecture with multiple "-omic" data sets and therapeutic response correlations. This approach may provide a deeper understanding of how cellular biochemistry defines therapeutic response. Such "-omic" portraits could inform rational anticancer agent screenings and drive personalized therapeutic approaches.

Original languageEnglish
Pages (from-to)676-685
Number of pages10
JournalMolecular Cancer Research
Volume11
Issue number6
DOIs
Publication statusPublished - Jun 2013

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Systems Analysis
Cell Line
Neoplasms
Proteins
Therapeutics
MicroRNAs
Phosphorylation
Somatomedin Receptors
Protein Array Analysis
Metabolomics
Phosphoproteins
Tumor Cell Line
Epidermal Growth Factor Receptor
Integrins
Pharmaceutical Preparations
Biochemistry
Antineoplastic Agents
Cell Survival
Protein Isoforms
Phosphotransferases

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

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Systems analysis of the NCI-60 cancer cell lines by alignment of protein pathway activation modules with "-OMIC" data fields and therapeutic response signatures. / Federici, Giulia; Gao, Xi; Slawek, Janusz; Arodz, Tomasz; Shitaye, Amanuel; Wulfkuhle, Julia D.; De Maria, Ruggero; Liotta, Lance A.; Petricoin, Emanuel F.

In: Molecular Cancer Research, Vol. 11, No. 6, 06.2013, p. 676-685.

Research output: Contribution to journalArticle

Federici, Giulia ; Gao, Xi ; Slawek, Janusz ; Arodz, Tomasz ; Shitaye, Amanuel ; Wulfkuhle, Julia D. ; De Maria, Ruggero ; Liotta, Lance A. ; Petricoin, Emanuel F. / Systems analysis of the NCI-60 cancer cell lines by alignment of protein pathway activation modules with "-OMIC" data fields and therapeutic response signatures. In: Molecular Cancer Research. 2013 ; Vol. 11, No. 6. pp. 676-685.
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