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.