2. Academic Validation
  3. Elesclomol-copper combination synergistically targets mitochondrial metabolism in cancer stem cells to overcome chemoresistance in PDAC

Elesclomol-copper combination synergistically targets mitochondrial metabolism in cancer stem cells to overcome chemoresistance in PDAC

  • Mol Ther. 2025 Sep 10:S1525-0016(25)00732-4. doi: 10.1016/j.ymthe.2025.09.004.
Qian Yu 1,  Ke Jiang 1,  Siyu Ma 1,  Quan Zheng 1,  Serena Tondi 2,  Chiara Reina 2,  Berina Šabanović 2,  Chenlei Wen 3,  Baiyong Shen 3,  Alexandra Aicher 4,  Haiyun Song 5,  Yinxing Ma 6,  Christopher Heeschen 7
Affiliations

Affiliations

  • 1 Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute - FPO - IRCCS, Candiolo, Turin, Italy.
  • 3 Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Precision Immunotherapy, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
  • 5 Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: songhaiyun@shsmu.edu.cn.
  • 6 Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: yinxingma@sjtu.edu.cn.
  • 7 Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute - FPO - IRCCS, Candiolo, Turin, Italy. Electronic address: christopher.heeschen@icloud.com.
PMID: 40931516 DOI: 10.1016/j.ymthe.2025.09.004
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive Cancer with a poor prognosis, partly due to Cancer Stem Cells (CSCs) that drive progression and treatment resistance. We explored the therapeutic potential of inducing Cuproptosis, a copper-dependent, regulated cell death, in CSC-enriched PDAC models. Using human and murine PDAC models, we evaluated elesclomol, a copper transport enhancer. Elesclomol alone had minimal effects; combined with copper chloride (CuCl2), it significantly and irreversibly reduced CSC phenotypes without affecting non-transformed cells. Mechanistically, only the combination raised intracellular copper ions 2- to 4-fold, decreased iron-sulfur cluster proteins, and caused lipoylated dihydrolipoamide S-acetyltransferase (DLAT) accumulation in mitochondria, triggering Cuproptosis, particularly in CSCs. It also selectively inhibited copper-dependent antioxidant SOD1 in PDAC cells, impairing oxidative stress defense and sensitizing them to copper-induced death. To enhance clinical relevance, CuCl2 was replaced with hollow mesoporous copper sulfide nanoparticles that release copper ions. Either combined with or loaded with elesclomol, these nanoparticles similarly increased copper levels and inhibited PDAC spheroid formation. In vivo, in aggressive immunocompetent murine PDAC models, this nanoparticle-based treatment significantly improved gemcitabine response. These findings identify nanoparticle-mediated Cuproptosis induction, combined with standard chemotherapy, as an innovative CSC-targeting strategy to improve PDAC outcomes, offering new hope for patients with PDAC.

Keywords

cancer stem cells; chemoresistance; copper; cuproptosis; elesclomol; mitochondria; nanoparticles; pancreatic cancer.

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