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.
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.