Abstract
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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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)