Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect

Annals of Surgery Open · 7 authors, 4 centres

AI SUMMARY

FIDELITY 100%

POPULATION43 treatment-naïve patients with gastrointestinal stromal tumors (GISTs) who underwent surgical resection.

INTERVENTIONMetabolomics profiling via 1H-NMR on surgical specimens, mRNA/protein assays for key enzymes, and dual-tracer 18F-FDG/11C-acetate PET imaging in 15 patients.

COMPARISONHigh-risk versus nonhigh-risk GISTs (based on modified NIH risk stratification).

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AGENT 01 · STRUCTURED SUMMARY

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TL;DR

This study analyzed the metabolism of 43 untreated gastrointestinal stromal tumors (GISTs) and found that aspartate is a key metabolite replenished by the TCA cycle and alanine/aspartate/glutamate metabolism. It also showed that high-risk GISTs preferentially use glucose (glycolysis) while nonhigh-risk tumors use acetate for fatty acid synthesis.

Full summary

900 CHARS

This human clinical cohort study investigated the metabolic landscape of treatment-naïve gastrointestinal stromal tumors (GISTs). Methods included 1H-NMR metabolomics on surgical specimens from 43 patients, mRNA and protein assays for GLUT1, HK2, ACSS2, and FASN, and dual-tracer PET imaging in 15 patients. Results showed GISTs are characterized by upregulated aspartate and glutamate and downregulated glucose, with the TCA cycle and alanine/aspartate/glutamate metabolism as leading pathways. High-risk tumors showed higher HK2 expression and 18F-FDG uptake, while nonhigh-risk tumors showed higher ACSS2 expression and 11C-acetate uptake. Nuclear ACSS2 was found only in high-risk cases. The study concludes aspartate acts as a de facto 'oncometabolite,' and glycolysis competes with ACSS2-mediated acetate metabolism for fatty acid synthesis, with glycolysis being the more aggressive phenotype.

PICO

PPOPULATION

43 treatment-naïve patients with gastrointestinal stromal tumors (GISTs) who underwent surgical resection.

IINTERVENTION

Metabolomics profiling via 1H-NMR on surgical specimens, mRNA/protein assays for key enzymes, and dual-tracer 18F-FDG/11C-acetate PET imaging in 15 patients.

OOUTCOME

Metabolic profiles, metabolite levels, enzyme expression, and in vivo tracer uptake.

STUDY TYPE

cohort

SPECIALTY

oncology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10406007

Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect

Annals of Surgery Open

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ABSTRACT

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 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. Keywords: acetate, aspartate, gastrointestinal stromal tumor, metabolomics, Warburg effect, TCA cycle

CITATION EXPORT

Ying-Chieh Lai, Gigin Lin, Kung-Chu Ho et al.. Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect. Annals of Surgery Open. (2022). https://doi.org/10.1097/AS9.0000000000000224

AUTHORS

7 · 4 CENTRES

Ying-Chieh Lai, Gigin Lin, Kung-Chu Ho, Kuan-Ying Lu, Cheng-Kun Tsai, Cheng-Yu Hung, Ta-Sen Yeh

From 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 Nuclear Medicine and Molecular Imaging Center, 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.