Glucose and glutamine metabolism in relation to mutational status in NSCLC histological subtypes.

Tineke W.H Meijer,Johannes H.A.M Kaanders,Michel Van Den Heuvel,Bastiaan Tops,Paul N Span,Johan Bussink,Jasper Lok,Monika G Looijen‐Salamon

doi:10.1111/1759-7714.13226

Abstract

BackgroundBoth hypoxia and oncogenic mutations rewire tumor metabolism. In this study, glucose and glutamine metabolism‐related markers were examined in stage I ‐ resectable stage IIIA non‐small cell lung cancer (NSCLC). Furthermore, expression of metabolism‐related markers was correlated with mutational status to examine mutations associated with rewired tumor metabolism.MethodsMutation analysis was performed for 97 tumors. Glucose and glutamine metabolism‐related marker expression was measured by immunofluorescent staining (protein) and qPCR (mRNA) (n = 81).ResultsGlutamine metabolism‐related markers were significantly higher in adeno‐ than squamous cell NSCLCs. Glucose transporter 1 (GLUT1) protein expression was higher in solid compared to lepidic adenocarcinomas (P < 0.01). In adenocarcinomas, mRNA expression of glutamine transporter SLC1A5 correlated with tumor size (r(p) = 0.41, P = 0.005). Furthermore, SLC1A5 protein expression was significantly higher in adenocarcinomas with worse pTNM stage (r(s) = 0.39, P = 0.009). EGFR‐mutated tumors showed lower GLUT1 protein (P = 0.017), higher glutaminase 2 (GLS2) protein (P = 0.025) and higher GLS2 mRNA expression (P = 0.004), compared to EGFR wild‐type tumors. GLS mRNA expression was higher in KRAS‐mutated tumors (P = 0.019). TP53‐mutated tumors showed higher GLUT1 expression (P = 0.009).ConclusionsNSCLC is a heterogeneous disease, with differences in mutational status and metabolism‐related marker expression between adeno‐ and squamous cell NSCLCs, and also within adenocarcinoma subtypes. GLUT1 and SLC1A5 expression correlate with aggressive tumor behavior in adenocarcinomas but not in squamous cell NSCLCs. Therefore, these markers could steer treatment modification for subgroups of adenocarcinoma patients. TP53, EGFR and KRAS mutations are associated with expression of glucose and glutamine metabolism‐related markers in NSCLC.

Highlights

Non-small cell lung cancer (NSCLC) is a heterogeneous disease regarding clinical, radiological, pathological, and molecular aspects.[1,2] In 2015, an update of the World Health Organization (WHO) classification was introduced, describing the major subtypes of adenocarcinomas demonstrating a predominantly lepidic, acinar, papillary, micropapillary, or solid growth pattern.[3]
Two tissue samples were missing for adenocarcinomas and one sample was missing for squamous cell carcinomas, resulting in 43 adenocarcinomas and 35 squamous cell carcinomas for glutamine metabolism-related marker analysis
Glucose transporter 1 (GLUT1) expression differed among adenocarcinoma subclassifications (P = 0.002), and was significantly higher in predominantly solid compared to predominantly lepidic adenocarcinomas (P < 0.01) (Fig 3)

Summary

Introduction

Non-small cell lung cancer (NSCLC) is a heterogeneous disease regarding clinical, radiological, pathological, and molecular aspects.[1,2] In 2015, an update of the World Health Organization (WHO) classification was introduced, describing the major subtypes of adenocarcinomas demonstrating a predominantly lepidic, acinar, papillary, micropapillary, or solid growth pattern.[3]. GLS1 has two splice variants: kidney-type glutaminase (KGA), and glutaminase C (GAC).[12] This metabolic transformation is the result of complex interactions between a hypoxic tumor microenvironment and oncogenic mutations, such as epidermal growth factor receptor (EGFR), TP53 and Kirsten rat sarcoma viral oncogene (KRAS).[9,13,14,15,16] Higher glucose utilization correlates with aggressive tumor behavior and treatment resistance including radiotherapy.[6] tumor metabolism might be exploited in future treatment strategies.

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Conclusion