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Updated: Oct 16, 2025

A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
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A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis

Published on: March 8, 2022

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The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor

Marie-Lise Lacombe1, Frederic Lamarche2, Olivier De Wever3

  • 1Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris, France.

BMC Biology
|October 22, 2021
PubMed
Abstract

Insights

Mitochondrial protein NME4 (NDPK-D) suppresses cancer metastasis. Loss of NME4 function in mitochondria promotes cancer cell invasion and metastasis, highlighting mitochondria

Area of Science:

  • Mitochondrial Biology
  • Cancer Research
  • Metastasis Suppression

Background:

  • Mitochondrial nucleoside diphosphate kinase (NDPK-D, also known as NME4 or NM23-H4) is an enzyme primarily located in the mitochondrial intermembrane space.
  • Its role in cancer progression and metastasis has not been fully elucidated.

Purpose of the Study:

  • To investigate the function of NDPK-D (NME4) in cancer metastasis.
  • To determine the impact of mitochondrial alterations on metastatic potential.

Main Methods:

  • Construction of loss-of-function mutants for NDPK-D (NME4) affecting kinase activity or membrane interaction.
  • Expression of wild-type and mutant NDPK-D in cancer cells, alongside RNA interference-mediated depletion.
  • Assessment of cell migration, invasion, and metastasis in immunocompromised mouse models.

Main Results:

  • Loss-of-function mutations and depletion of NDPK-D (NME4) induced epithelial-mesenchymal transition, enhancing cell migration and invasion.
  • Mice injected with cells expressing mutant NDPK-D exhibited increased metastasis compared to those with wild-type.
  • Metastatic reprogramming involved mitochondrial fragmentation, a shift to glycolysis, increased ROS, and altered mitochondrial metabolism, promoting pro-metastatic signaling.

Conclusions:

  • NME4 functions as a novel metastasis suppressor gene, uniquely localized to mitochondria.
  • Mitochondria play a critical role in regulating metastatic dissemination.
  • NME4 expression correlates with reduced epithelial-mesenchymal transition markers and improved clinical outcomes in human cancers.
Keywords:
InvasionMetabolic reprogrammingMetastasisMitochondrial dynamicsNME4Nucleoside diphosphate kinasePrognosis biomarkerRetrograde signaling

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