Metabolic classification of non-small cell lung cancer patient-derived xenografts by a digital pathology approach: A pilot study

Abstract

IntroductionGenetically characterized patient-derived tumor xenografts (PDX) are a valuable resource to understand the biological complexity of cancer and to investigate new therapeutic approaches. Previous studies, however, lack information about metabolic features of PDXs, which may limit testing of metabolism targeting drugs.MethodsIn this pilot study, we investigated by immunohistochemistry (IHC) expression of five essential metabolism-associated markers in a set of lung adenocarcinoma PDX samples previously established and characterized. We exploited digital pathology to quantify expression of the markers and correlated results with tumor cell proliferation, angiogenesis and time of PDX growth in mice.ResultsOur results indicate that the majority of the analyzed PDX models rely on oxidative phosphorylation (OXPHOS) metabolism, either alone or in combination with glucose metabolism. Double IHC enabled us to describe spatial expression of the glycolysis-associated monocarboxylate transporter 4 (MCT4) marker and the OXPHOS-associated glutaminase (GLS) marker. GLS expression was associated with cell proliferation and with expression of liver-kinase B1 (LKB1), a tumor suppressor involved in the regulation of multiple metabolic pathways. Acetyl CoA carboxylase (ACC) was associated with the kinetics of PDX growth.ConclusionAlbeit limited by the small number of samples and markers analyzed, metabolic classification of existing collections of PDX by this mini panel will be useful to inform pre-clinical testing of metabolism-targeting drugs.

CIP2A induces PKM2 tetramer formation and oxidative phosphorylation in non-small cell lung cancer

“…Human NSCLC tumors have enhanced glucose oxidation 4 , 62 , but the mechanisms remain to be addressed. We found that in NSCLC cells CIP2A knockdown significantly increased the glycolysis rate and lactate production and inhibited OXPHOS, whereas CIP2A overexpression suppressed glycolysis and increased OXPHOS.…”