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Identifying Sex Differences in Lung Adenocarcinoma Using Multi-Omics Integrative Protein Signaling Networks.

Chen Chen1, Enakshi Saha1, Jonas Fischer1,2

  • 1Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.

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This study reveals sex-specific molecular differences in lung adenocarcinoma (LUAD) by analyzing proteomic and transcriptomic data. Findings highlight potential sex-specific drugs for personalized LUAD cancer therapy.

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APOLLOCPTACLung adenocarcinomaPRISMTCGAdrug repurposingmulti-omicspost-translational modificationsprotein signaling networksex differences

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Area of Science:

  • Oncology
  • Genomics
  • Proteomics
  • Systems Biology

Background:

  • Lung adenocarcinoma (LUAD) shows sex-based disparities in incidence, prognosis, and treatment response.
  • These differences suggest underlying molecular mechanisms that are not fully understood.
  • Investigating sex-specific molecular pathways is crucial for advancing personalized cancer therapies.

Purpose of the Study:

  • To conduct an integrative multi-omics analysis contrasting transcriptomes and proteomes between sexes in LUAD.
  • To identify sex-biased molecular signaling networks and druggable targets.
  • To discover potential sex-specific therapeutic strategies for LUAD.

Main Methods:

  • Utilized Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) datasets.
  • Employed TIGER for analyzing TCGA-LUAD expression data to identify sex-biased transcription factor (TF) activity.
  • Applied PTM-SEA to CPTAC-LUAD proteomics data to detect sex-biased kinase activity.
  • Constructed a kinase-TF signaling network and analyzed the PRISM drug screening database.

Main Results:

  • Identified significant sex biases in transcription factor and kinase activity.
  • Revealed a kinase-TF signaling network linking to cancer-related processes.
  • Discovered sex-specific biases in clinically relevant TFs and kinases (e.g., NR3C1, AR, AURKA).
  • Identified potential sex-specific drugs, including glucocorticoid receptor agonists and aurora kinase inhibitors.

Conclusions:

  • Multi-omics network analysis reveals critical sex-specific molecular differences in LUAD.
  • Findings underscore the importance of integrating sex as a biological variable in cancer research.
  • The study provides a foundation for developing personalized, sex-specific therapeutic strategies for LUAD.