Colorectal cancer cell-derived exosomes induce metabolic reprogramming of cancer-associated fibroblasts to promote colorectal cancer growth
Urea cycle (UC) dysfunction drives tumorigenesis and poor prognosis, yet its role in tumor-stroma crosstalk is unclear. Here we show that colorectal cancer (CRC) cells reprogram UC metabolism in cancer-associated fibroblasts (CAFs) via CRC-derived exosomes. Reprogrammed CAFs support CRC cell growth by providing UC metabolites, especially arginine (Arg). Depriving CRC cells of Arg halts their growth and simultaneously increases their reliance on putrescine while up-regulating ornithine decarboxylase (ODC), the polyamine-biosynthesis gatekeeper. Our study illustrates the UC metabolic interaction between CAFs and CRC cells and demonstrates the potential therapeutic utility of Arg restriction and ODC blockade combination treatment for colorectal cancer.
Authors
- Guopeng Pan (ORCID: https://orcid.org/0009-0001-7059-644X)
- Youwei Huang (ORCID: https://orcid.org/0000-0001-8350-1991)
- Fang Wang (ORCID: https://orcid.org/0009-0008-5160-7909)
- Zexiong Cheng
- Fan Xing (ORCID: https://orcid.org/0000-0001-7278-2513)
- Jun Liu (ORCID: https://orcid.org/0000-0002-5275-2656)
- Xiangyu Wang (ORCID: https://orcid.org/0000-0001-8605-0727)
- Yiwei Wang (ORCID: https://orcid.org/0000-0003-1314-1833)
- Kai Li (ORCID: https://orcid.org/0000-0002-4040-8604)
- Qing Li (ORCID: https://orcid.org/0000-0002-4982-1024)
- Rui Wang (ORCID: https://orcid.org/0000-0002-2404-7917)
- Xi Lin (ORCID: https://orcid.org/0000-0003-3911-9677)
- Yuqin Li
- Yuequan Zeng (ORCID: https://orcid.org/0009-0005-2297-1515)
- C.P. Wu
Institutions
- Sun Yat-sen University (CN)
- Jinan University (CN)
- Guangdong Medical College (CN)
- Sixth Affiliated Hospital of Sun Yat-sen University (CN)
- Southern Medical University Shenzhen Hospital (CN)
- Guangdong Academy of Medical Sciences (CN)
- Guangdong Provincial People's Hospital (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Discover Oncology
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1007/s12672-025-03914-0
- Primary Topic
- Polyamine Metabolism and Applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Basic and Applied Basic Research Foundation of Guangdong Province