2. Academic Validation
  3. Screening of patient-derived organoids identifies mitophagy as a cell-intrinsic vulnerability in colorectal cancer during statin treatment

Screening of patient-derived organoids identifies mitophagy as a cell-intrinsic vulnerability in colorectal cancer during statin treatment

  • Cell Rep Med. 2025 Apr 15;6(4):102039. doi: 10.1016/j.xcrm.2025.102039.
Zhi-Hang Tao 1,  Ji-Xuan Han 1,  Jia Xu 2,  Enhao Zhao 2,  Ming Wang 2,  Zheng Wang 2,  Xiao-Lin Lin 3,  Xiu-Ying Xiao 3,  Jie Hong 1,  Haoyan Chen 1,  Ying-Xuan Chen 1,  Hui-Min Chen 4,  Jing-Yuan Fang 5
Affiliations

Affiliations

  • 1 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 2 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 3 Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: huimin.chan@foxmail.com.
  • 5 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: jingyuanfang@sjtu.edu.cn.
PMID: 40154491 DOI: 10.1016/j.xcrm.2025.102039
Abstract

Statins, commonly used to lower Cholesterol, are associated with improved prognosis in colorectal Cancer (CRC), though their effectiveness varies. This study investigates the anti-cancer effects of atorvastatin in CRC using patient-derived organoids (PDOs) and PDO-derived xenograft (PDOX) models. Our findings reveal that atorvastatin induces mitochondrial dysfunction, leading to Apoptosis in Cancer cells. In response, Cancer cells induce Mitophagy to clear damaged mitochondria, enhancing survival and reducing statin efficacy. Analysis of a clinical cohort confirms mitophagy's role in diminishing statin effectiveness. Importantly, inhibiting Mitophagy significantly enhances the anti-cancer effects of atorvastatin in CRC PDOs, xenograft models, and azoxymethane (AOM)-dextran sulfate sodium (DSS) mouse models. These findings identify Mitophagy as a critical pro-survival mechanism in CRC during statin treatment, providing insights into the variable responses observed in epidemiological studies. Targeting this vulnerability through combination therapy can elicit potent therapeutic responses.

Keywords

colorectal cancer; mitophagy; patient-derived organoids; statin.

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