Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect

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

doi:10.1097/AS9.0000000000000224

Aspartate and Acetate Fuel Gastrointestinal Stromal Tumors Beyond the Warburg Effect

Ann Surg Open. 2022 Dec 7;3(4):e224. doi: 10.1097/AS9.0000000000000224. eCollection 2022 Dec.

Authors

Ying-Chieh Lai^{1

2}, Gigin Lin^{1

2}, Kung-Chu Ho³, Kuan-Ying Lu^{1

2}, Cheng-Kun Tsai², Cheng-Yu Hung², Ta-Sen Yeh⁴

Affiliations

¹ From the Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linko, Chang Gung University, Taoyuan, Taiwan.
² Department of Metabolomics Core Lab, Chang Gung Memorial Hospital at Linko, Chang Gung University, Taoyuan, Taiwan.
³ Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital at Linko, Chang Gung University, Taoyuan, Taiwan.
⁴ Department of Surgery, Chang Gung Memorial Hospital at Linko, Chang Gung University, Taoyuan, Taiwan.

Abstract

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.

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

Grants and funding

Disclosure: The authors declare that they have nothing to disclose.