Abstract 545: NOTCH1 co-expression analysis reveals novel insights underlying its opposing effects as an oncogenic and tumor suppressor in lung cancer

Abstract

Abstract Background: Aberrations in the family of Notch receptors (1, 2, 3, and 4) have been implicated in a range of solid tumors, including lung cancer. NOTCH1 biology is complex where Notch plays an oncogenic and tumor suppressor role in lung adenocarcinoma and lung squamous cell carcinoma, respectively. Although the role of Notch in cancer development and progression has received increased appreciation in recent years, there is still a lack of understanding of the mechanisms underlying these opposing activities in lung cancer. Methods: The Cancer Genome Atlas datasets were used to examine gene co-expression patterns of Notch1 in lung adenocarcinoma and lung squamous cell carcinoma. Biological pathways implicated by gene families were assessed using functional annotation tools (DAVID, ToppGene, and IPA). In vitro and in vivo knockdown studies assessed the functional role of Notch1. Results: This novel co-expression analysis supports the hypothesis that NOTCH1 is co-expressed with different genes in lung adenocarcinoma and squamous cell carcinoma. Knockdown of Notch1 in vitro and in vivo support our in silico finding of opposing effects of NOTCH1. Our analysis implicates genes associated with metabolic pathways, immune pathways, angiogenesis and cell cycle that may underlie the differential role of NOTCH1 in lung adenocarcinoma and squamous cell carcinoma. In vitro and in vivo studies support our bioinformatics analysis. Conclusion: These results demonstrate different NOTCH1 gene co-expression patterns in lung adenocarcinoma and squamous cell carcinoma. These findings provide novel insights underlying the context-dependent role of Notch as an oncogene and tumor suppressor in subtypes of lung cancer. Understanding the similarities and differences in co-expression patterns reveal novel insights, suggesting that tumor intrinsic and extrinsic pathways may underlie the dual role of NOTCH1 in lung cancer. Recognition of the mechanisms underlying NOTCH1 opposing roles in cancer may help direct development of Notch-targeted therapies as a monotherapy or in combination with approaches focusing on the tumor microenvironment. Citation Format: Sara L. Sinicropi-Yao, David P. Carbone, Kevin R. Coombes, Joseph M. Amann, David Lopez Lopez. NOTCH1 co-expression analysis reveals novel insights underlying its opposing effects as an oncogenic and tumor suppressor in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 545.