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Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect
Metabolic reprogramming is closely linked to the tumorigenesis and drug resistance of gastrointestinal stromal tumors (GISTs). Mapping the metabolic orbit of GISTs is a prerequisite if intervention against the metabolic vulnerability of refractory GISTs is desirable. METHODS: A total of 43 patients...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Wolters Kluwer Health, Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406007/ https://www.ncbi.nlm.nih.gov/pubmed/37600289 http://dx.doi.org/10.1097/AS9.0000000000000224 |
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author | Lai, Ying-Chieh Lin, Gigin Ho, Kung-Chu Lu, Kuan-Ying Tsai, Cheng-Kun Hung, Cheng-Yu Yeh, Ta-Sen |
author_facet | Lai, Ying-Chieh Lin, Gigin Ho, Kung-Chu Lu, Kuan-Ying Tsai, Cheng-Kun Hung, Cheng-Yu Yeh, Ta-Sen |
author_sort | Lai, Ying-Chieh |
collection | PubMed |
description | Metabolic reprogramming is closely linked to the tumorigenesis and drug resistance of gastrointestinal stromal tumors (GISTs). Mapping the metabolic orbit of GISTs is a prerequisite if intervention against the metabolic vulnerability of refractory GISTs is desirable. METHODS: A total of 43 patients with treatment-naïve GISTs who had undergone surgical resections were enrolled, on whom a metabolomics profile detected from surgical specimens was constructed based on the (1)H-nuclear magnetic resonance (NMR) platform. The mRNA and protein levels of GLUT1, HK2, ACSS2, and FASN were assayed. Dual-tracer (18)F-FDG/11C-acetate PET imaging was introduced before surgery in 15 patients. RESULTS: (1)H-NMR-based metabolomics revealed that GISTs were characterized by upregulation of glutamate, ascorbate, aspartate and glycine and downregulation of choline, creatine, glucose and glycerol. Bioinformatics analysis showed that the TCA cycle and alanine, aspartate, and glutamate metabolism were the two leading pathways. High- and nonhigh-risk (including intermediate-, low-, and very low-risk) GISTs preferentially displayed upregulation of HK2 and ACSS2, respectively, echoed by in vivo imaging that high- and nonhigh-risk GISTs preferentially exhibited higher uptake of (18)F-FDG and (11)C-acetate, respectively, while (18)F-FDG and (11)C-acetate were complementary to each other. Nuclear ACSS2 was exclusively identified in high-risk GISTs. CONCLUSION: We describe a metabolic landscape of GISTs that read aspartate as a de facto “oncometabolite,” which was replenished via the TCA cycle and alanine, aspartate, and glutamate metabolism. Glycolysis and ACSS2-mediated acetate metabolism competed and complemented fatty acid synthesis, although glycolysis remained an aggressive phenotype. |
format | Online Article Text |
id | pubmed-10406007 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Wolters Kluwer Health, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-104060072023-08-18 Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect Lai, Ying-Chieh Lin, Gigin Ho, Kung-Chu Lu, Kuan-Ying Tsai, Cheng-Kun Hung, Cheng-Yu Yeh, Ta-Sen Ann Surg Open Original Study Metabolic reprogramming is closely linked to the tumorigenesis and drug resistance of gastrointestinal stromal tumors (GISTs). Mapping the metabolic orbit of GISTs is a prerequisite if intervention against the metabolic vulnerability of refractory GISTs is desirable. METHODS: A total of 43 patients with treatment-naïve GISTs who had undergone surgical resections were enrolled, on whom a metabolomics profile detected from surgical specimens was constructed based on the (1)H-nuclear magnetic resonance (NMR) platform. The mRNA and protein levels of GLUT1, HK2, ACSS2, and FASN were assayed. Dual-tracer (18)F-FDG/11C-acetate PET imaging was introduced before surgery in 15 patients. RESULTS: (1)H-NMR-based metabolomics revealed that GISTs were characterized by upregulation of glutamate, ascorbate, aspartate and glycine and downregulation of choline, creatine, glucose and glycerol. Bioinformatics analysis showed that the TCA cycle and alanine, aspartate, and glutamate metabolism were the two leading pathways. High- and nonhigh-risk (including intermediate-, low-, and very low-risk) GISTs preferentially displayed upregulation of HK2 and ACSS2, respectively, echoed by in vivo imaging that high- and nonhigh-risk GISTs preferentially exhibited higher uptake of (18)F-FDG and (11)C-acetate, respectively, while (18)F-FDG and (11)C-acetate were complementary to each other. Nuclear ACSS2 was exclusively identified in high-risk GISTs. CONCLUSION: We describe a metabolic landscape of GISTs that read aspartate as a de facto “oncometabolite,” which was replenished via the TCA cycle and alanine, aspartate, and glutamate metabolism. Glycolysis and ACSS2-mediated acetate metabolism competed and complemented fatty acid synthesis, although glycolysis remained an aggressive phenotype. Wolters Kluwer Health, Inc. 2022-12-07 /pmc/articles/PMC10406007/ /pubmed/37600289 http://dx.doi.org/10.1097/AS9.0000000000000224 Text en Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
spellingShingle | Original Study Lai, Ying-Chieh Lin, Gigin Ho, Kung-Chu Lu, Kuan-Ying Tsai, Cheng-Kun Hung, Cheng-Yu Yeh, Ta-Sen Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect |
title | Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect |
title_full | Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect |
title_fullStr | Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect |
title_full_unstemmed | Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect |
title_short | Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect |
title_sort | aspartate and acetate fuel gastrointestinal stromal tumors beyond the warburg effect |
topic | Original Study |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406007/ https://www.ncbi.nlm.nih.gov/pubmed/37600289 http://dx.doi.org/10.1097/AS9.0000000000000224 |
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