Affiliations
- The Frontier Center for Cell Response, State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China.
- The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- School of Statistics and Data Science, LPMC and KLMDASR, Nankai University, Tianjin, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
- CNBG-Nankai University Joint Research and Development Center, Tianjin, China.
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- Department of International Medical Services, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
- School of Statistics and Data Science, LPMC and KLMDASR, Nankai University, Tianjin, China. Electronic address: huggs@nankai.edu.cn.
- The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. Electronic address: dul@ioz.ac.cn.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. Electronic address: dul@ioz.ac.cn.
- CNBG-Nankai University Joint Research and Development Center, Tianjin, China. Electronic address: dul@ioz.ac.cn.
- The Frontier Center for Cell Response, State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China. Electronic address: chenq@nankai.edu.cn.
PMID: 38291304 DOI: 10.1038/s43018-023-00715-8
Abstract
Acquired drug resistance is a major challenge for cancer therapy and is the leading cause of cancer mortality; however, the mechanisms of drug resistance are diverse and the strategy to specifically target drug-resistant cancer cells remains an unmet clinical issue. Here, we established a colorectal cancer-derived organoid biobank and induced acquired drug resistance by repeated low-level exposures of chemo-agents. Chemosensitivity profiling and transcriptomic analysis studies revealed that chemoresistant cancer-derived organoids exhibited elevated expression of LGR4 and activation of the Wnt signaling pathway. Further, we generated a monoclonal antibody (LGR4-mAb) that potently inhibited LGR4-Wnt signaling and found that treatment with LGR4-mAb notably sensitized drug-induced ferroptosis. Mechanistically, LGR4-dependent Wnt signaling transcriptionally upregulated SLC7A11, a key inhibitor of ferroptosis, to confer acquired drug resistance. Our findings reveal that targeting of Wnt signaling by LGR4-mAb augments ferroptosis when co-administrated with chemotherapeutic agents, demonstrating a potential opportunity to fight refractory and recurrent cancers.
