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

Katherine Sellers, Thaddeus D. Allen, Michael Bousamra, Jin Lian 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

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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: Analysis of multiple transcriptomics data from human samples identified a SCC-distinguishing enzyme gene signature. SCC tumours from patients infused with [U-13C]-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.

Original languageEnglish
Pages (from-to)51-64
Number of pages14
JournalBritish Journal of Cancer
Volume121
Issue number1
DOIs
StatePublished - Jul 2 2019

Bibliographical note

Funding Information:
Funding: This work was supported in part by National Science Foundation EPSCoR infrastructure grants EPS-0447479 (to T.W.-M.F.); NIH grants 5P01CA163223 (to A.N.L and T.W.-M.F) 1R01CA118434-01A2, 1RO1CA101199-01, 3R01CA118434-02S1 and 1R01ES022191-01 (to T.W.-M. F.), and 1U24DK097215-01A1 (to R.M.H., T.W.M.F. and A. N.L.); the University of Louisville CTSPGP/ARRA grant 20044; the Kentucky Lung Cancer Research Program grants OGMB090354B1 and OGMB101380 (to T.W.-M.F. and A.N.L.). This work was also supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001223), the UK Medical Research Council (FC001223), and the Wellcome Trust (FC001223).

Publisher Copyright:
© 2019, The Author(s).

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Metabolic reprogramming and Notch activity distinguish between non-small cell lung cancer subtypes'. Together they form a unique fingerprint.

Cite this