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Metabolic reprogramming and Notch activity distinguish between non-small cell lung cancer subtypes

Year: 2019
Type: article
Abstract: BACKGROUND: Previous studies suggested that the metabolism is differently reprogrammed in the major subtypes of non-small cell lung cancer (NSCLC), squamous cell carcinomas (SCC) and adenocarcinomas (AdC). However, a comprehensive analysis of this differential metabolic reprogramming is lacking. METHODS: Publicly available gene expression data from human lung cancer samples and cell lines were analysed. Stable isotope resolved metabolomics were performed on SCC and ADC tumours in human patients and in freshly resected tumour slices. RESULTS: C]-glucose and SCC tissue slices incubated with stable isotope tracers demonstrated differential glucose and glutamine catabolism compared to AdCs or non-cancerous lung, confirming increased activity through pathways defined by the SCC metabolic gene signature. Furthermore, the upregulation of Notch target genes was a distinguishing feature of SCCs, which correlated with the metabolic signature. Notch and MYC-driven murine lung tumours recapitulated the SCC-distinguishing metabolic reprogramming. However, the differences between SCCs and AdCs disappear in established cell lines in 2D culture. CONCLUSIONS: Our data emphasise the importance of studying lung cancer metabolism in vivo. They also highlight potential targets for therapeutic intervention in SCC patients including differentially expressed enzymes that catalyse reactions in glycolysis, glutamine catabolism, serine, nucleotide and glutathione biosynthesis.
DOI: 10.1038/s41416-019-0464-z
Authors: Katherine Sellers, Thaddeus D. Allen, Michael Bousamra, JinLian Tan, Andrés Méndez-Lucas, Wei Lin, Nourdine Bah, Yelena Chernyavskaya, James I. MacRae, Richard M. Higashi, Andrew N. Lane, Teresa W.-M. Fan, Mariia O. Yuneva
Institutions: The Francis Crick Institute, Agios Pharmaceuticals (United States), University of California, San Francisco, Seton Medical Center, BioLink Life Sciences, University of Louisville, University of Kentucky
Language: English
Subfield: Cancer Research
Open Access status: hybrid
Estimated APC paid: $3,300
Funders: National Science Foundation, University of Louisville, Wellcome Trust, Francis Crick Institute, Cancer Research UK, University College London, National Institutes of Health, Medical Research Council, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, Office of Experimental Program to Stimulate Competitive Research
Awards: Systems Biochemistry in Lung Cancer: Toward a Mechanistic Understanding of NSCLC, G1649690196, G180086439, G2793002436, Building Kentucky's New Economy with EPSCoR, G3768580956, Integrated Chemoselective and Informatic Platform for Large-Scale Metabolomics, G4002584958, G4344689229, Resource Center for Stable Isotope-Resolved Metabolomics, G5980734565, Biochemical Mechanisms of Se Anticancer Activity in Lung, Selenium Prevention of Tobacco Smoke-Induced Lung Cancer, G8020133240, G8577269960
OpenAlex ID: W2945234874
FWCI: 2.057
Cites: 66
Cited by: 57
Related to: 10