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

Autor: Sellers K; The Francis Crick Institute, London, UK.; Agios Pharmaceuticals, Cambridge, MA, USA., Allen TD; G.W. Hooper Research Foundation, University of California, San Francisco, CA, USA.; Tradewind BioScience, Inc., Daly City, CA, USA., Bousamra M 2nd; James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.; Baptist Health Medical Group, Thoracic Surgery, New Albany, IN, USA., Tan J; James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.; Dental-Oral Immunity & Infectious Diseases, Dept. Medicine, University of Louisville, Louisville, KY, USA., Méndez-Lucas A; The Francis Crick Institute, London, UK., Lin W; The Francis Crick Institute, London, UK., Bah N; The Francis Crick Institute, London, UK., Chernyavskaya Y; Center for Environmental and Systems Biochemistry, Dept. Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA., MacRae JI; The Francis Crick Institute, London, UK., Higashi RM; Center for Environmental and Systems Biochemistry, Dept. Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA., Lane AN; Center for Environmental and Systems Biochemistry, Dept. Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA., Fan TW; Center for Environmental and Systems Biochemistry, Dept. Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA. teresa.fan@uky.edu., Yuneva MO; The Francis Crick Institute, London, UK. Mariia.Yuneva@crick.ac.uk.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2019 Jul; Vol. 121 (1), pp. 51-64. Date of Electronic Publication: 2019 May 22.
DOI: 10.1038/s41416-019-0464-z
Abstrakt: 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: Analysis of multiple transcriptomics data from human samples identified a SCC-distinguishing enzyme gene signature. SCC tumours from patients infused with [U- 13 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.
Databáze: MEDLINE
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