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Malic Enzyme 1 Absence in Synovial Sarcoma Shifts Antioxidant System Dependence and Increases Sensitivity to
Caitlyn B Brashears1, Bethany C Prudner1, Richa Rathore1
1Division of Medical Oncology, Washington University in St. Louis, St. Louis, Missouri.
Purpose:
To investigate the metabolism of synovial sarcoma (SS) and elucidate the effect of malic enzyme 1 absence on SS redox homeostasis.
Experimental Design:
ME1 expression was measured in SS clinical samples, SS cell lines, and tumors from an SS mouse model. The effect of ME1 absence on glucose metabolism was evaluated utilizing Seahorse assays, metabolomics, and C13 tracings. The impact of ME1 absence on SS redox homeostasis was evaluated by metabolomics, cell death assays with inhibitors of antioxidant systems, and measurements of intracellular reactive oxygen species (ROS). The susceptibility of ME1-null SS to ferroptosis induction was interrogated in vitro and in vivo.
Results:
ME1 absence in SS was confirmed in clinical samples, SS cell lines, and an SS tumor model. Investigation of SS glucose metabolism revealed that ME1-null cells exhibit higher rates of glycolysis and higher flux of glucose into the pentose phosphate pathway (PPP), which is necessary to produce NADPH. Evaluation of cellular redox homeostasis demonstrated that ME1 absence shifts dependence from the glutathione system to the thioredoxin system. Concomitantly, ME1 absence drives the accumulation of ROS and labile iron. ROS and iron accumulation enhances the susceptibility of ME1-null cells to ferroptosis induction with inhibitors of xCT (erastin and ACXT-3102). In vivo xenograft models of ME1-null SS demonstrate significantly increased tumor response to ACXT-3102 compared with ME1-expressing controls.
Conclusions:
These findings demonstrate the translational potential of targeting redox homeostasis in ME1-null cancers and establish the preclinical rationale for a phase I trial of ACXT-3102 in SS patients. See related commentary by Subbiah and Gan, p. 3408.
Insights
Malic enzyme 1 (ME1) absence in synovial sarcoma (SS) alters glucose metabolism and redox homeostasis, increasing susceptibility to ferroptosis. ME1-null SS shows enhanced response to xCT inhibitors, supporting clinical trials.
Area of Science:
- Oncology
- Cancer Metabolism
- Redox Biology
Background:
- Synovial sarcoma (SS) is a rare soft tissue sarcoma with complex metabolic dependencies.
- Understanding SS metabolism is crucial for developing targeted therapies.
- Malic enzyme 1 (ME1) plays a role in cellular metabolism and redox balance.
Purpose of the Study:
- To investigate the metabolic alterations in synovial sarcoma (SS) associated with the absence of malic enzyme 1 (ME1).
- To elucidate the impact of ME1 absence on SS redox homeostasis and susceptibility to ferroptosis.
- To establish the preclinical rationale for targeting ME1-null SS with xCT inhibitors.
Main Methods:
- ME1 expression analysis in SS clinical samples, cell lines, and mouse models.
- Seahorse assays, metabolomics, and C13 tracings to evaluate glucose metabolism.
- Cell death assays, ROS measurements, and ferroptosis induction studies (in vitro and in vivo).
Main Results:
- ME1 absence in SS correlates with increased glycolysis and pentose phosphate pathway (PPP) flux, enhancing NADPH production.
- ME1-null SS exhibits a shift in redox dependence from the glutathione to the thioredoxin system, leading to ROS and labile iron accumulation.
- ME1-null SS demonstrates increased sensitivity to ferroptosis inducers, with significant tumor response to ACXT-3102 in vivo.
Conclusions:
- ME1 absence significantly impacts SS metabolism and redox homeostasis, creating vulnerabilities.
- Targeting redox homeostasis via xCT inhibition (e.g., ACXT-3102) is a promising therapeutic strategy for ME1-null SS.
- These findings support the initiation of a Phase I clinical trial for ACXT-3102 in SS patients.
