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.
Highlights
Glucose transporters are the first and rate-limiting step for cellular glucose utilization, a process often exacerbated in tumor cells that enables their growth and proliferation (Ancey et al, 2018; Lunt and Vander Heiden, 2011)
From a human tissue microarray comprising 18 cases of stage IB-IIB lung adenocarcinoma (LUAD) and 18 cases of stage IA-IIB lung squamous cell carcinoma (LUSC), GLUT1 protein was detected in all tumors
In the immunocompetent KrasLSL-G12D/WT; Trp53Flox/Flox (KP) mouse model where tumors consist of pure LUADs all harboring Trp53 gene deletion, RNA sequencing analyses of bulk tumor samples revealed a predominance of NMF4-like lesions (Figure 1—figure supplement 1c)
Summary
Glucose transporters are the first and rate-limiting step for cellular glucose utilization, a process often exacerbated in tumor cells that enables their growth and proliferation (Ancey et al, 2018; Lunt and Vander Heiden, 2011). In solid cancers, tumor cell growth can be fueled by nutrients other than glucose, or by using transporter-independent metabolic processes including autophagy and macropinocytosis (Commisso et al, 2013; Karsli-Uzunbas et al, 2014; Romero et al, 2017; Son et al, 2013). We exploited the KrasLSL-G12D/WT; Trp53Flox/Flox (KP) mouse model of lung adenocarcinoma to explore the importance of glucose transporters, expressed by tumor cells, in disease development. We show that the deletion of Glut or Glut is not sufficient to decrease tumor progression, which is only affected significantly upon combined Glut and Glut loss
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
