Abstract 4403: FDG uptake in human lung adenocarcinoma associated with invasion through the hexosamine biosynthesis pathway
Authors: Zhang Weiruo , Bouchard Gina , Yu Alice , Shafiq Majid , Jamali Mehran , Shrager Joseph , Ayers Kelsey , Nair Viswam S. , Gentles Andrew , Diehn Maximilian , Quon Andrew , Napel Sandy , Plevritis Sylvia 
Published: July 2017

Abstract
Introduction
Metabolic reprogramming is a cancer hallmark that is not fully understood. Moreover, increasing evidence suggests that metabolic dysregulation is histology-specific, particularly in the case of non-small cell lung cancer (NSCLC). In this study, we investigated the differences in glucose metabolism between the two major histology subtypes of NSCLC, namely adenocarcinoma (AD) and squamous cell carcinoma (SQ). We explored transcriptomics in association with FDG-PET SUVmax (maximum standardized uptake value), a common clinical marker of glucose uptake in cancer.
Methods
We identified metabolically-associated differentially expressed genes (DEGs) by histology subtypes using RNAseq data from resected tumors in our study cohort of 127 NSCLC patients (96 AD and 31 SQ) and validated the DEGs on The Cancer Genome Atlas. We also identified gene-enriched cellular processes correlated with SUVmax separately for AD and SQ. We validated our findings in public domain cell line microarray data. In a separate cohort of 40 NSCLC patients (20 patients overlap with study cohort) whose tumors were sorted by cell type (cancer, endothelial, fibroblast and immune cells), we identified specific cell types where the genes of interest were expressed.
Results
Metabolically-associated DEGs in AD were enriched in the hexosamine biosynthesis pathway (HBP), which is involved in glycosylating proteins related to invasion. SUVmax correlated genes in AD were enriched for epithelial-mesenchymal transition (EMT) and extracellular matrix remodeling. In particular, GFPT2 (the rate-limiting gene in HBP) and 4 EMT-related glycoprotein genes were highly correlated with SUVmax, suggesting potency of HBP for EMT related glucose metabolic reprogramming. We validated the findings on cell line microarray data (GSE49644) before and after TGF-β induced EMT, showing that many genes in HBP increased after induced EMT, while genes in the glycolysis pathway and the pentose phosphate pathway (PPP) were unchanged or reduced. HBP genes and many SUVmax correlated EMT genes were most highly expressed in tumor-associated fibroblasts compared to other cells in the tumor microenvironment. In SQ, metabolically-associated DEGs were enriched in the glycolysis pathway and PPP. SUVmax correlated genes were enriched for cell development.
Conclusion
An integrative analysis of PET-RNAseq showed that in AD glucose uptake was related to invasion through metabolic reprogramming of HBP. In SQ, glucose uptake was associated with glycolysis and higher proliferation potential. Our work confirms that metabolic dysregulation in NSCLC is histology-specific and extends the finding to identify cellular processes associated with FDG uptake that differ by histology as well. Understanding histology-specific differences of tumor metabolism provides new insights into tumor behavior that can have implications for anti-cancer therapy.
Citation Format: Weiruo Zhang, Gina Bouchard, Alice Yu, Majid Shafiq, Mehran Jamali, Joseph Shrager, Kelsey Ayers, Viswam S. Nair, Andrew Gentles, Maximilian Diehn, Andrew Quon, Sandy Napel, Sylvia Plevritis. FDG uptake in human lung adenocarcinoma associated with invasion through the hexosamine biosynthesis pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4403. doi:10.1158/1538-7445.AM2017-4403