Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase–deficient renal cell carcinoma
Liang Zheng, … , Jin Zhang, Eyal Gottlieb
Liang Zheng, … , Jin Zhang, Eyal Gottlieb
Published April 13, 2023
Citation Information: J Clin Invest. 2023;133(11):e165028. https://doi.org/10.1172/JCI165028.
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Research Article Metabolism Oncology

Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase–deficient renal cell carcinoma

Abstract

Germline or somatic loss-of-function mutations of fumarate hydratase (FH) predispose patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection there is no effective therapy for metastatic FH-deficient RCC, an accurate method for early diagnosis is needed. Although MRI or CT scans are offered, they cannot differentiate FH-deficient tumors from other RCCs. Therefore, finding noninvasive plasma biomarkers suitable for rapid diagnosis, screening, and surveillance would improve clinical outcomes. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed plasma metabolomics analysis and identified 2 tumor-derived metabolites, succinyl-adenosine and succinic-cysteine, as excellent plasma biomarkers for early diagnosis. These 2 molecules reliably reflected the FH mutation status and tumor mass. We further identified the enzymatic cooperativity by which these biomarkers are produced within the tumor microenvironment. Longitudinal monitoring of patients demonstrated that these circulating biomarkers can be used for reporting on treatment efficacy and identifying recurrent or metastatic tumors.

Authors

Liang Zheng, Zi-Ran Zhu, Tal Sneh, Wei-Tuo Zhang, Zao-Yu Wang, Guang-Yu Wu, Wei He, Hong-Gang Qi, Hang Wang, Xiao-Yu Wu, Jonatan Fernández-García, Ifat Abramovich, Yun-Ze Xu, Jin Zhang, Eyal Gottlieb

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Figure 6

Circulating suc-cys is a product of the enzymatic cascade of the GGT1-DPEP1 axis.

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Circulating suc-cys is a product of the enzymatic cascade of the GGT1-DP...
(A) Schematic representation of intravenous injection of suc-GSH into mice and the metabolic fate in vivo. (B) Analysis of the in vitro assay of suc-GSH in mouse plasma. (C) Analysis of the in vitro enzymatic conversion of suc-GSH into suc-cys-gly by the recombinant proteins. (D) Analysis of the in vitro enzymatic conversion of suc-cys-gly into suc-cys by the recombinant human proteins. (E) Assessment of the ability of the indicated mouse tissue homogenates to catabolize the conversion of suc-GSH into suc-cys-gly and suc-cys. (F) mRNA levels of different transpeptidases and dipeptidases in various mouse tissues (normalized to liver) were determined by quantitative PCR (qPCR). (G) Immunoblotting was used to measure GGT1 and DPEP1 expression. All experiments were performed independently 3 times. All data are presented as the mean ± SEM.