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<p>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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月14日

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  • Jin Heon Jeon,
  • Mark D. Slayton,
  • Ben Krinkel,
  • Olamide Animasahun,
  • Ajay Shankaran,
  • Fulei Wuchu,
  • Minal Nenwani,
  • Zackariah Farah,
  • Julia Burke,
  • Abhinav Achreja,
  • Brisilda Nilaj,
  • Kerslee Kohagen,
  • Yi-Hsien Eu,
  • Alyssa Rosenfeld,
  • Mason Collard,
  • Liwei Bao,
  • Xu Cheng,
  • Celina Kleer,
  • Christopher Squire,
  • Kerry Loomes,
  • Deepak Nagrath,
  • Sofia D. Merajver

摘要

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.

Graphical Abstract