Adaptation to cystine limitation stress confers a targetable lipid metabolism vulnerability in pancreatic ductal adenocarcinoma
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.
Authors
- Scot R. Kimball (ORCID: https://orcid.org/0000-0002-2149-7189)
- Bo Ni (ORCID: https://orcid.org/0000-0001-9154-1213)
- Yunkun Dang (ORCID: https://orcid.org/0000-0002-8206-0271)
- Ashley E. Shay (ORCID: https://orcid.org/0000-0003-4501-680X)
- Yu Shan (ORCID: https://orcid.org/0000-0003-3121-5170)
- Chenyang Meng (ORCID: https://orcid.org/0000-0002-1052-353X)
- Shengyu Yang (ORCID: https://orcid.org/0000-0002-7933-6118)
- Girish H. Rajacharya (ORCID: https://orcid.org/0000-0003-4811-9505)
- Kun-Ming Chen (ORCID: https://orcid.org/0000-0002-3820-6149)
- Mingjun Tan (ORCID: https://orcid.org/0000-0003-2210-6319)
- Shiqi Zhang (ORCID: https://orcid.org/0000-0001-9751-7652)
- Guangcong Shen
- Bin Qiao (ORCID: https://orcid.org/0000-0001-7581-9078)
- Rifah Rownak Tanshee (ORCID: https://orcid.org/0009-0006-5074-3146)
- Xiuchao Wang
- Tianxing Zhou (ORCID: https://orcid.org/0009-0006-0150-1343)
- Yunzhan Li
- Min Jeong Wang
- Boyang Fu
- Pankaj K. Singh
- Qin Li
- Yongjie Xie
- Guanshi Zhang
- Zekun Li
- Dongxiao Sun
- Jihui Hao
Institutions
- Pennsylvania State University (US)
- Tianjin University (CN)
- The University of Texas at San Antonio Health Science Center (US)
- Yunnan University (CN)
- Tianjin Medical University Cancer Institute and Hospital (CN)
- University of Oklahoma Health Sciences Center (US)
- Penn State Milton S. Hershey Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-31
- DOI
- https://doi.org/10.1038/s41467-025-68099-0
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00