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<p>Cystine/cysteine is critical for antioxidant response and sulfur metabolism in cancer cells and is one of the most depleted amino acids in the microenvironment of pancreatic ductal adenocarcinoma (PDAC). The effects of cystine limitation stress (CLS) on PDAC progression are poorly understood. Here we report that adaptation to CLS (CLSA) promotes PDAC cell proliferation and tumor growth through translational upregulation of the oxidative pentose phosphate pathway (OxPPP). OxPPP activates the de novo synthesis of nucleotides and fatty acids to support tumor growth. On the other hand, CLSA-mediated lipidomic reprogramming depends on triacylglycerides synthesis and lipid droplet formation to mitigate lipotoxicity. Through drug screening, we identify lomitapide as an inhibitor of CLSA PDAC tumor growth and a potent sensitizer of chemotherapy. Lomitapide inhibits triacylglycerides synthesis to interfere with CLSA and chemotherapy-induced lipidomic reprogramming. Taken together, we demonstrate that CLSA promotes PDAC tumor growth through metabolic reprogramming and lomitapide could be used to target the dysregulated lipid metabolism in PDAC.</p>

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Adaptation to cystine limitation stress confers a targetable lipid metabolism vulnerability in pancreatic ductal adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月31日

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  • Yunzhan Li,
  • Zekun Li,
  • Qin Li,
  • Dongxiao Sun,
  • Bo Ni,
  • Mingjun Tan,
  • Ashley E. Shay,
  • Min Wang,
  • Chenyang Meng,
  • Guangcong Shen,
  • Boyang Fu,
  • Yueying Shan,
  • Shiqi Zhang,
  • Rifah Rownak Tanshee,
  • Tianxing Zhou,
  • Yongjie Xie,
  • Kun-Ming Chen,
  • Bin Qiao,
  • Yunkun Dang,
  • Scot R. Kimball,
  • Guanshi Zhang,
  • Girish H. Rajacharya,
  • Pankaj K. Singh,
  • Xiuchao Wang,
  • Jihui Hao,
  • Shengyu Yang

摘要

Cystine/cysteine is critical for antioxidant response and sulfur metabolism in cancer cells and is one of the most depleted amino acids in the microenvironment of pancreatic ductal adenocarcinoma (PDAC). The effects of cystine limitation stress (CLS) on PDAC progression are poorly understood. Here we report that adaptation to CLS (CLSA) promotes PDAC cell proliferation and tumor growth through translational upregulation of the oxidative pentose phosphate pathway (OxPPP). OxPPP activates the de novo synthesis of nucleotides and fatty acids to support tumor growth. On the other hand, CLSA-mediated lipidomic reprogramming depends on triacylglycerides synthesis and lipid droplet formation to mitigate lipotoxicity. Through drug screening, we identify lomitapide as an inhibitor of CLSA PDAC tumor growth and a potent sensitizer of chemotherapy. Lomitapide inhibits triacylglycerides synthesis to interfere with CLSA and chemotherapy-induced lipidomic reprogramming. Taken together, we demonstrate that CLSA promotes PDAC tumor growth through metabolic reprogramming and lomitapide could be used to target the dysregulated lipid metabolism in PDAC.