Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect
Background:. 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 o...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Health
2022-12-01
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| Series: | Annals of Surgery Open |
| Online Access: | http://journals.lww.com/10.1097/AS9.0000000000000224 |
| _version_ | 1827979233786331136 |
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| author | Ying-Chieh Lai, MD Gigin Lin, MD, PhD Kung-Chu Ho, MD Kuan-Ying Lu, MS Cheng-Kun Tsai, PhD Cheng-Yu Hung, PhD Ta-Sen Yeh, MD, PhD |
| author_facet | Ying-Chieh Lai, MD Gigin Lin, MD, PhD Kung-Chu Ho, MD Kuan-Ying Lu, MS Cheng-Kun Tsai, PhD Cheng-Yu Hung, PhD Ta-Sen Yeh, MD, PhD |
| author_sort | Ying-Chieh Lai, MD |
| collection | DOAJ |
| description | Background:. 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 1H-nuclear magnetic resonance (NMR) platform. The mRNA and protein levels of GLUT1, HK2, ACSS2, and FASN were assayed. Dual-tracer 18F-FDG/11C-acetate PET imaging was introduced before surgery in 15 patients.
Results:. 1H-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 18F-FDG and 11C-acetate, respectively, while 18F-FDG and 11C-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. |
| first_indexed | 2024-04-09T21:34:03Z |
| format | Article |
| id | doaj.art-bfd17b5f463b469baa230ef38ada5a8c |
| institution | Directory Open Access Journal |
| issn | 2691-3593 |
| language | English |
| last_indexed | 2024-04-09T21:34:03Z |
| publishDate | 2022-12-01 |
| publisher | Wolters Kluwer Health |
| record_format | Article |
| series | Annals of Surgery Open |
| spelling | doaj.art-bfd17b5f463b469baa230ef38ada5a8c2023-03-27T06:41:35ZengWolters Kluwer HealthAnnals of Surgery Open2691-35932022-12-0134e22410.1097/AS9.0000000000000224202212000-00022Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg EffectYing-Chieh Lai, MD0Gigin Lin, MD, PhD1Kung-Chu Ho, MD2Kuan-Ying Lu, MS3Cheng-Kun Tsai, PhD4Cheng-Yu Hung, PhD5Ta-Sen Yeh, MD, PhD6From the * Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linko, Chang Gung University, Taoyuan, TaiwanFrom the * Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linko, Chang Gung University, Taoyuan, Taiwan‡ Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital at Linko, Chang Gung University, Taoyuan, TaiwanFrom the * Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linko, Chang Gung University, Taoyuan, Taiwan† Department of Metabolomics Core Lab, Chang Gung Memorial Hospital at Linko, Chang Gung University, Taoyuan, Taiwan† Department of Metabolomics Core Lab, Chang Gung Memorial Hospital at Linko, Chang Gung University, Taoyuan, Taiwan§ Department of Surgery, Chang Gung Memorial Hospital at Linko, Chang Gung University, Taoyuan, Taiwan.Background:. 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 1H-nuclear magnetic resonance (NMR) platform. The mRNA and protein levels of GLUT1, HK2, ACSS2, and FASN were assayed. Dual-tracer 18F-FDG/11C-acetate PET imaging was introduced before surgery in 15 patients. Results:. 1H-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 18F-FDG and 11C-acetate, respectively, while 18F-FDG and 11C-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.http://journals.lww.com/10.1097/AS9.0000000000000224 |
| spellingShingle | Ying-Chieh Lai, MD Gigin Lin, MD, PhD Kung-Chu Ho, MD Kuan-Ying Lu, MS Cheng-Kun Tsai, PhD Cheng-Yu Hung, PhD Ta-Sen Yeh, MD, PhD Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect Annals of Surgery Open |
| 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 |
| url | http://journals.lww.com/10.1097/AS9.0000000000000224 |
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