Sara L Sinicropi-Yao1, Joseph M Amann2, David Lopez Y Lopez2, Ferdinando Cerciello3, Kevin R Coombes4, David P Carbone5. 1. Department of Internal Medicine, James Thoracic Center, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio; Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio. 2. Department of Internal Medicine, James Thoracic Center, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. 3. Department of Internal Medicine, James Thoracic Center, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio; Department of Oncology, Center of Hematology and Oncology, Comprehensive Cancer Center Zürich, University Hospital Zürich, Zürich, Switzerland. 4. Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio. 5. Department of Internal Medicine, James Thoracic Center, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. Electronic address: David.Carbone@osumc.edu.
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.
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.
Authors: Xia Xu; Lingling Huang; Christopher Futtner; Brian Schwab; Rishi R Rampersad; Yun Lu; Thomas A Sporn; Brigid L M Hogan; Mark W Onaitis Journal: Genes Dev Date: 2014-09-01 Impact factor: 11.361
Authors: Shankha Satpathy; Karsten Krug; Pierre M Jean Beltran; Sara R Savage; Francesca Petralia; Chandan Kumar-Sinha; Yongchao Dou; Boris Reva; M Harry Kane; Shayan C Avanessian; Suhas V Vasaikar; Azra Krek; Jonathan T Lei; Eric J Jaehnig; Tatiana Omelchenko; Yifat Geffen; Erik J Bergstrom; Vasileios Stathias; Karen E Christianson; David I Heiman; Marcin P Cieslik; Song Cao; Xiaoyu Song; Jiayi Ji; Wenke Liu; Kai Li; Bo Wen; Yize Li; Zeynep H Gümüş; Myvizhi Esai Selvan; Rama Soundararajan; Tanvi H Visal; Maria G Raso; Edwin Roger Parra; Özgün Babur; Pankaj Vats; Shankara Anand; Tobias Schraink; MacIntosh Cornwell; Fernanda Martins Rodrigues; Houxiang Zhu; Chia-Kuei Mo; Yuping Zhang; Felipe da Veiga Leprevost; Chen Huang; Arul M Chinnaiyan; Matthew A Wyczalkowski; Gilbert S Omenn; Chelsea J Newton; Stephan Schurer; Kelly V Ruggles; David Fenyö; Scott D Jewell; Mathangi Thiagarajan; Mehdi Mesri; Henry Rodriguez; Sendurai A Mani; Namrata D Udeshi; Gad Getz; James Suh; Qing Kay Li; Galen Hostetter; Paul K Paik; Saravana M Dhanasekaran; Ramaswamy Govindan; Li Ding; Ana I Robles; Karl R Clauser; Alexey I Nesvizhskii; Pei Wang; Steven A Carr; Bing Zhang; D R Mani; Michael A Gillette Journal: Cell Date: 2021-08-05 Impact factor: 66.850