Co-Expression Analysis Reveals Mechanisms Underlying the Varied Roles of NOTCH1 in NSCLC

Sara L. Sinicropi-Yao, Joseph M. Amann, David Lopez Y. Lopez, Ferdinando Cerciello, Kevin R. Coombes, David P. Carbone

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Introduction: Notch receptor family dysregulation can be tumor promoting or suppressing depending on cellular context. Our studies shed light on the mechanistic differences that are responsible for NOTCH1’s opposing roles in lung adenocarcinoma and lung squamous cell carcinoma. Methods: We integrated transcriptional patient-derived datasets with gene co-expression analyses to elucidate mechanisms behind NOTCH1 function in subsets of NSCLC. Differential co-expression was examined using hierarchical clustering and principal component analysis. Enrichment analysis was used to examine pathways associated with the underlying transcriptional networks. These pathways were validated in vitro and in vivo. Endogenously epitope-tagged NOTCH1 was used to identify novel interacting proteins. Results: NOTCH1 co-expressed genes in lung adenocarcinoma and squamous carcinoma were distinct and associated with either angiogenesis and immune system pathways or cell cycle control and mitosis pathways, respectively. Tissue culture and xenograft studies of lung adenocarcinoma and lung squamous models with NOTCH1 knockdown showed growth differences and opposing effects on these pathways. Differential NOTCH1 interacting proteins were identified as potential mediators of these differences. Conclusions: Recognition of the opposing role of NOTCH1 in lung cancer, downstream pathways, and interacting proteins in each context may help direct the development of rational NOTCH1 pathway-dependent targeted therapies for specific tumor subsets of NSCLC.

Original languageEnglish (US)
Pages (from-to)223-236
Number of pages14
JournalJournal of Thoracic Oncology
Volume14
Issue number2
DOIs
StatePublished - Feb 2019
Externally publishedYes

Keywords

  • Affinity purification-mass spectrometry/mass spectrometry
  • Co-expression
  • Genomics
  • Immune function
  • Lung cancer
  • Notch

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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