Head and Neck Squamous Cell Carcinoma Metabolism Draws on Glutaminolysis, and Stemness Is Specifically Regulated by Glutaminolysis via Aldehyde Dehydrogenase

Abstract

Cancer cells use alternate energetic pathways; however, cancer stem cell (CSC) metabolic energetic pathways are unknown. The purpose of this study was to define the metabolic characteristics of head and neck cancer at different points of its pathogenesis with a focus on its CSC compartment. UPLC-MS/MS-profiling and GC-MS-validation studies of human head and neck cancer tissue, saliva, and plasma were used in conjunction with in vitro and in vivo models to carry out this investigation. We identified metabolite biomarker panels that distinguish head and neck cancer from healthy controls, and confirmed involvement of glutamate and glutaminolysis. Glutaminase, which catalyzes glutamate formation from glutamine, and aldehyde dehydrogenase (ALDH), a stemness marker, were highly expressed in primary and metastatic head and neck cancer tissues, tumorspheres, and CSC versus controls. Exogenous glutamine induced stemness via glutaminase, whereas inhibiting glutaminase suppressed stemness in vitro and tumorigenesis in vivo. Head and neck CSC (CD44hi/ALDHhi) exhibited higher glutaminase, glutamate, and sphere levels than CD44lo/ALDHlo cells. Glutaminase drove transcriptional and translational ALDH expression, and glutamine directed even CD44lo/ALDHlo cells toward stemness. Glutaminolysis regulates tumorigenesis and CSC metabolism via ALDH. These findings indicate that glutamate is an important marker of cancer metabolism whose regulation via glutaminase works in concert with ALDH to mediate cancer stemness. Future analyses of glutaminolytic-ALDH driven mechanisms underlying tumorigenic transitions may help in the development of targeted therapies for head and neck cancer and its CSC compartment.

Integrated Non-targeted and Targeted Metabolomics Uncovers Amino Acid Markers of Oral Squamous Cell Carcinoma

“…The study on metabolomics of cancer tissue specimens is helpful to improve the diagnosis and treatment of OSCC. Currently, metabolomics studies of oral cancer use primarily biological fluids (e.g., plasma, urine, saliva) and cell lines (18)(19)(20)(21)(22), because biofluids and cell lines are readily available. Most biofluids-based metabolomics studies are relatively quantitative, without in-depth study on a specific metabolic type and a specific metabolite, such as amino acid metabolism and the specific content of a certain amino acid.…”

Metabolic Biomarkers of Squamous Cell Carcinoma of the Aerodigestive Tract: A Systematic Review and Quality Assessment

“…All studies were Phase I biomarker discovery studies. Of the 30 included studies, 18 were from Asia and the Far East [8,9,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26], seven from Europe [27][28][29][30][31][32][33], three from North America [34][35][36], and two from the Middle East [37,38]. ASCC tumour sites identified were the head and neck (n = 17), oesophageal (n = 8), and lung (n = 5).…”

“…ASCC tumour sites identified were the head and neck (n = 17), oesophageal (n = 8), and lung (n = 5). The majority of studies compared patients with cancer to normal controls and or benign conditions [16,25,26,28,29,34,[38][39][40][41][42][43].…”

“…Sample types used in these studies were tissue (n = 10), saliva (n = 13), plasma (n = 13), urine (n = 5), and breath (n = 6). Several studies used more than one analytical platform [34,35,38,40] and/or sample types for analysis [34,35] (Table 1). Eight studies used targeted methods, and 22 studies untargeted methods.…”

“…Reporting of clinical demographics was not consistent in each study. Of the 30 studies, only 10 fully reported all clinical demographics [28,30,34,35,38,41,43,47,49,51], 13 reported at least patient age, gender, and clinical stage [16,25,26,31,36,39,40,42,45,46,48,52,53]. Seven studies did not report differences in metabolite profile at different tumour stages [24,27,29,32,36,37,46].…”