Interplay between malic enzyme 2, de novo serine synthesis, and the malate-aspartate shuttle drives metabolic adaptation in triple-negative breast cancer

TL;DR

This study explores how inhibiting the enzyme ME2 affects the metabolism and growth of triple-negative breast cancer cells, offering potential for new precision cancer therapies.

Contribution

The study reveals the interplay between ME2, serine synthesis, and the malate-aspartate shuttle in TNBC, supported by structural analysis of ME2 inhibition.

Findings

ME2 inhibition slowed tumor growth and improved survival in TNBC xenograft models.

ME2 knockdown altered mitochondrial respiration, glycolysis, and serine/glycine metabolism.

The crystal structure of ME2 bound to NPD-389 was determined, revealing key inhibitory interactions.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer with poor clinical outcomes. Malic enzyme 2 (ME2) is a mitochondrial enzyme that catalyzes the conversion of malate to pyruvate and has been proposed as a therapeutic target. ME2 is highly expressed in many cell types including TNBC cells. We sought to define the molecular and cellular consequences of ME2 inhibition to facilitate its clinical translation. Here, we systematically evaluated the cellular and molecular effects of ME2 knockdown (ME2kd) in multiple TNBC models. ME2kd had heterogeneous effects on proliferation, migration, and metabolic flexibility in TNBC cell lines. ME2kd MDA-MB-468 xenografts in nude mice grew significantly slower and conferred prolonged host survival. ME2kd caused distinct shifts in mitochondrial respiration and glycolysis, whereas metabolomic and transcriptomic analyses revealed altered tricarboxylic acid (TCA) cycle flux, glutamine consumption, and serine/glycine metabolism, partly through changes in malate-aspartate shuttle (MAS) activity. The interplay between ME2, the serine synthesis pathway and the MAS was investigated with metabolite deprivation and co-knockdown assays. Importantly, we determined the crystal structure of ME2 bound to the small-molecule inhibitor NPD-389 and identified the binding interactions that drive the inhibitory response. These findings help to clarify the role of ME2 in TNBC phenotypes and highlight the therapeutic potential of ME2 inhibition in precision oncology.

The online version contains supplementary material available at 10.1186/s40170-025-00410-5.

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