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<p>Metastatic cancer cells, originating from cancer stem cells with metastatic capacity, utilize nutrient flexibility to navigate the challenges of the metastatic cascade. However, the nutrient required to maintain the stemness potentials of metastatic cancer cells remains unclear. Here, we reveal that metastatic breast cancer cells sustain stemness and initiate metastasis upon detachment by taking up and oxidizing lactate. In detached metastasizing breast cancer cells, lactate is incorporated into the tricarboxylic acid cycle, boosting oxidative phosphorylation, and promoting the stemness potentials via α-KG-DNMT3B-mediated <i>SOX2</i> hypomethylation. Moreover, lactate is taken up and oxidized in mitochondria by the CD147/MCT1/LDHB complex, which correlates with stemness potentials and tumor metastasis in patients with breast cancer. An intracellularly expressed single-chain variable fragment targeting mitochondrial CD147 (mito-CD147 scFv) effectively disrupts the mitochondrial CD147/MCT1/LDHB complex, inhibits lactate-induced stemness potential, depletes circulating breast cancer cells, and reduces metastatic burden, suggesting promising clinical applications in reducing lactate-fueled metastasis.</p>

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Lactate mitochondrial oxidation drives stemness potential in metastatic breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月18日

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  • Jia-Jia Zhang,
  • Ruo-Fei Tian,
  • Chang-Geng Song,
  • Rui Liu,
  • Duo He,
  • Gai-Qin Zhang,
  • Xin-Yu Fan,
  • Zi-Chuan Duan,
  • Kun Zhang,
  • Tian-Jiao Zhang,
  • Ya-Tong Chen,
  • Jian Zhang,
  • Ke Wang,
  • Ju-Mei Zhao,
  • Xiang-Min Yang,
  • Zhi-Nan Chen,
  • Ling Li

摘要

Metastatic cancer cells, originating from cancer stem cells with metastatic capacity, utilize nutrient flexibility to navigate the challenges of the metastatic cascade. However, the nutrient required to maintain the stemness potentials of metastatic cancer cells remains unclear. Here, we reveal that metastatic breast cancer cells sustain stemness and initiate metastasis upon detachment by taking up and oxidizing lactate. In detached metastasizing breast cancer cells, lactate is incorporated into the tricarboxylic acid cycle, boosting oxidative phosphorylation, and promoting the stemness potentials via α-KG-DNMT3B-mediated SOX2 hypomethylation. Moreover, lactate is taken up and oxidized in mitochondria by the CD147/MCT1/LDHB complex, which correlates with stemness potentials and tumor metastasis in patients with breast cancer. An intracellularly expressed single-chain variable fragment targeting mitochondrial CD147 (mito-CD147 scFv) effectively disrupts the mitochondrial CD147/MCT1/LDHB complex, inhibits lactate-induced stemness potential, depletes circulating breast cancer cells, and reduces metastatic burden, suggesting promising clinical applications in reducing lactate-fueled metastasis.