Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth

Caroline Contat; Pierre-Benoit Ancey; Nadine Zangger; Silvia Sabatino; Justine Pascual; Stéphane Escrig; Louise Jensen; Christine Goepfert; Bernard Lanz; Mario Lepore; Rolf Gruetter; Anouk Rossier; Sabina Berezowska; Christina Neppl; Inti Zlobec; Stéphanie Clerc-Rosset; Graham William Knott; Jeffrey C Rathmell; E Dale Abel; Anders Meibom; Etienne Meylan

doi:10.7554/eLife.53618

Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth

Elife. 2020 Jun 23:9:e53618. doi: 10.7554/eLife.53618.

Authors

Caroline Contat^{1

2}, Pierre-Benoit Ancey^{1

2}, Nadine Zangger^{1

2

3}, Silvia Sabatino^{1

2}, Justine Pascual^{1

2}, Stéphane Escrig⁴, Louise Jensen⁴, Christine Goepfert⁵, Bernard Lanz⁶, Mario Lepore⁷, Rolf Gruetter^{6

7}, Anouk Rossier^{1

2}, Sabina Berezowska⁸, Christina Neppl⁸, Inti Zlobec⁸, Stéphanie Clerc-Rosset⁹, Graham William Knott⁹, Jeffrey C Rathmell¹⁰, E Dale Abel¹¹, Anders Meibom^{4

12}, Etienne Meylan^{1

2}

Affiliations

¹ Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
² Swiss Cancer Center Léman, Lausanne, Switzerland.
³ Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁴ Laboratory for Biological Geochemistry, School of Architecture, Civil and Environmental Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
⁵ Institute of Animal Pathology (COMPATH), University of Bern, CH-3012 Bern, and Histology Core Facility, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
⁶ Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
⁷ Center for Biomedical Imaging (CIBM), Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
⁸ Institute of Pathology, University of Bern, Bern, Switzerland.
⁹ BioEM Facility, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
¹⁰ Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, United States.
¹¹ Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, United States.
¹² Center for Advanced Surface Analysis, Faculty of Geosciences and Environment, University of Lausanne, Lausanne, Switzerland.

Abstract

Glucose utilization increases in tumors, a metabolic process that is observed clinically by ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET). However, is increased glucose uptake important for tumor cells, and which transporters are implicated in vivo? In a genetically-engineered mouse model of lung adenocarcinoma, we show that the deletion of only one highly expressed glucose transporter, Glut1 or Glut3, in cancer cells does not impair tumor growth, whereas their combined loss diminishes tumor development. ¹⁸F-FDG-PET analyses of tumors demonstrate that Glut1 and Glut3 loss decreases glucose uptake, which is mainly dependent on Glut1. Using ¹³C-glucose tracing with correlated nanoscale secondary ion mass spectrometry (NanoSIMS) and electron microscopy, we also report the presence of lamellar body-like organelles in tumor cells accumulating glucose-derived biomass, depending partially on Glut1. Our results demonstrate the requirement for two glucose transporters in lung adenocarcinoma, the dual blockade of which could reach therapeutic responses not achieved by individual targeting.

Keywords: NanoSIMS; cancer biology; genetically engineered mouse model of cancer; glucose transporters; human; lamellar bodies; lung adenocarcinoma; mouse.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung / physiopathology*
Animals
Cell Line, Tumor
Female
Fluorodeoxyglucose F18 / chemistry
Gene Deletion*
Glucose / metabolism*
Glucose Transporter Type 1 / genetics*
Glucose Transporter Type 1 / metabolism
Glucose Transporter Type 2 / genetics*
Glucose Transporter Type 2 / metabolism
Humans
Male
Mice
Mice, Transgenic
Microscopy, Electron, Scanning
Microscopy, Electron, Transmission
Positron-Emission Tomography
Spectrometry, Mass, Secondary Ion

Substances

Glucose Transporter Type 1
Glucose Transporter Type 2
SLC2A1 protein, human
SLC2A2 protein, human
Slc2a1 protein, mouse
Slc2a2 protein, mouse
Fluorodeoxyglucose F18
Glucose

Associated data

GEO/GSE138757

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding