GFPT2-Expressing Cancer-Associated Fibroblasts Mediate Metabolic Reprogramming in Human Lung Adenocarcinoma

Abstract

Metabolic reprogramming of the tumor microenvironment is recognized as a cancer hallmark. To identify new molecular processes associated with tumor metabolism, we analyzed the transcriptome of bulk and flow-sorted human primary non-small cell lung cancer (NSCLC) together with FDG-PET scans, which provide a clinical measure of glucose uptake. Tumors with higher glucose uptake were functionally enriched for molecular processes associated with invasion in adenocarcinoma and cell growth in squamous cell carcinoma (SCC). Next, we identified genes correlated to glucose uptake that were predominately overexpressed in a single cell-type comprising the tumor microenvironment. For SCC, most of these genes were expressed by malignant cells, whereas in adenocarcinoma, they were predominately expressed by stromal cells, particularly cancer-associated fibroblasts (CAF). Among these adenocarcinoma genes correlated to glucose uptake, we focused on glutamine-fructose-6-phosphate transaminase 2 (), which codes for the glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation. was predictive of glucose uptake independent of GLUT1, the primary glucose transporter, and was prognostically significant at both gene and protein level. We confirmed that normal fibroblasts transformed to CAF-like cells, following TGFβ treatment, upregulated HBP genes, including, with less change in genes driving glycolysis, pentose phosphate pathway, and TCA cycle. Our work provides new evidence of histology-specific tumor stromal properties associated with glucose uptake in NSCLC and identifies as a critical regulator of tumor metabolic reprogramming in adenocarcinoma. These findings implicate the hexosamine biosynthesis pathway as a potential new therapeutic target in lung adenocarcinoma. .

Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy

“…The rate-limiting enzyme of this pathway is glutamine-fructose amidotransferase 1/2 (GFAT1/2), which is responsible for controlling the flux of metabolites through this pathway. The HBP is highly utilized in a number of cancers, and its inhibition by either targeting GFAT1/2 or by preventing utilization of glutamine (using a glutamine analog, 6-diazo-5-oxo-lnorleucine [DON]) results in tumor regression (27)(28)(29).…”

CaMeRe: A Novel Tool for Inference of Cancer Metabolic Reprogramming

“…Glutamine-Fructose-6-Phosphate Transaminase (GFPT1), also alternatively named Glutamine:fructose-6-phosphate amidotransferase 1 (GFAT1), is a well-known glucose-related protein, which catalyze the reaction from the beta-Dfructofuranose 6-phosphate to the L-glutamate (25, 26) ( Figure 5) and acts as the rate-limiting enzyme in the HBP FIGURE 4 | The result of searching from D-glyceraldehyde 3-phosphate to 1,3-bisphospho-D-glycerate exhibits in the first line whose bottleneck largely surpasses the second line's, which means the expression level of the enzyme involved in the reaction route 1 is much higher than that in the reaction route 2 and suggests the conspicuousness of reaction route 1. that is also one of the protein glycosylation pathways (27). The expression of GFPT1 is highly upregulated in many cancers like pancreatic cancer compared to the normal tissue (28), since it can generate the uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to keep the level of glycosylated proteins (24) and regulate the function of proteins.…”

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

“…Cancer‐associated fibroblasts (CAFs) are the most abundant cell populations within the TME playing multiple key roles in progression of cancer, including immunosuppression (Li et al, ), cancer growth (Zhang et al, ), and metastasis (Ahirwar et al, ). CAFs create a stiffened extracellular matrix (ECM) that in an indirect way contributes to the activation of ERK pathway.…”