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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.
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Location
Identifier / keyword
Title
Colorectal cancer cell-derived exosomes induce metabolic reprogramming of cancer-associated fibroblasts to promote colorectal cancer growth
Author
Pan, Guopeng 1 ; Cheng, Zexiong 1 ; Wang, Yiwei 2 ; Wu, Changxi 3 ; Wang, Fang 4 ; Li, Qing 1 ; Wang, Xiangyu 1 ; Zeng, Yuequan 4 ; Li, Yuqin 1 ; Li, Kai 5 ; Lin, Xi 1 ; Xing, Fan 6 ; Huang, Youwei 7 ; Liu, Jun 8 ; Wang, Rui 9
1 Jinan University, Department of Pharmacology, School of Medicine, Guangzhou, China (GRID:grid.258164.c) (ISNI:0000 0004 1790 3548)
2 Jinan University, Department of Microbiology and Immunology, School of Medicine, Guangzhou, China (GRID:grid.258164.c) (ISNI:0000 0004 1790 3548)
3 Southern Medical University, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471)
4 Jinan University, Department of Pharmacology, School of Medicine, Guangzhou, China (GRID:grid.258164.c) (ISNI:0000 0004 1790 3548); Southern Medical University, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471)
5 The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangdong Research Institute of Gastroenterology, Guangzhou, China (GRID:grid.488525.6)
6 Southern Medical University, Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471)
7 Guangdong Medical University, Department of Pathophysiology, School of Basic Medicine, Dongguan, China (GRID:grid.410560.6) (ISNI:0000 0004 1760 3078)
8 Southern Medical University Shenzhen Hospital, Department of Science Innovation, Shenzhen, China (GRID:grid.488521.2)
9 Southern Medical University, Department of Radiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471)
1 Jinan University, Department of Pharmacology, School of Medicine, Guangzhou, China (GRID:grid.258164.c) (ISNI:0000 0004 1790 3548)
2 Jinan University, Department of Microbiology and Immunology, School of Medicine, Guangzhou, China (GRID:grid.258164.c) (ISNI:0000 0004 1790 3548)
3 Southern Medical University, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471)
4 Jinan University, Department of Pharmacology, School of Medicine, Guangzhou, China (GRID:grid.258164.c) (ISNI:0000 0004 1790 3548); Southern Medical University, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471)
5 The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangdong Research Institute of Gastroenterology, Guangzhou, China (GRID:grid.488525.6)
6 Southern Medical University, Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471)
7 Guangdong Medical University, Department of Pathophysiology, School of Basic Medicine, Dongguan, China (GRID:grid.410560.6) (ISNI:0000 0004 1760 3078)
8 Southern Medical University Shenzhen Hospital, Department of Science Innovation, Shenzhen, China (GRID:grid.488521.2)
9 Southern Medical University, Department of Radiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471)
Discover Oncology; New York
Volume
16
Issue
1
Pages
2146
Publication year
2025
Publication date
Dec 2025
Place of publication
New York
Country of publication
Netherlands
Publication subject
e-ISSN
27306011
Source type
Scholarly Journal
Language of publication
English
Document type
Journal Article
Publication history
Online publication date
2025-11-24
Milestone dates
2025-10-17 (Registration); 2025-06-02 (Received); 2025-10-17 (Accepted)
Publication history
First posting date
24 Nov 2025
ProQuest document ID
3275424391
Document URL
https://www.proquest.com/scholarly-journals/colorectal-cancer-cell-derived-exosomes-induce/docview/3275424391/se-2?accountid=208611
Copyright
© The Author(s) 2025. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Last updated
2025-11-26
Database
ProQuest One Academic