Cancer-associated fibroblast-derived urea cycle metabolites promote colorectal cancer growth

Urea cycle (UC) dysfunction is linked to both tumorigenesis and poor prognosis in multiple cancers. However, the role of UC metabolism in tumor-stroma crosstalk is unclear. Here, we show that colorectal cancer (CRC) cells induce reprogramming of UC metabolism in cancer-associated fibroblasts (CAFs), which is mediated by CRC-derived exosomes. Reprogrammed CAFs support CRC cell growth by providing UC metabolites, especially arginine (Arg). Consequently, Arg deprivation resulted in growth inhibition of CRC cells. Furthermore, we found that Arg deprivation increases CRC's dependence on putrescine (Put) and upregulates the expression of the polyamine biosynthetic rate-limiting enzyme ornithine decarboxylase (ODC). Combined Arg deprivation and ODC inhibitor effectively restrains CRC cell growth. 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. Overall design: To explore the influence of CRC-derived exosomes on CAFs, we performed RNA sequencing (RNA-seq) in primary CAFs treated with HCT116-secreted exosomes (HCT116 Exo) or vehicle control.

尿素循环（Urea cycle, UC）功能异常与多种癌症的肿瘤发生及不良预后密切相关，但目前尿素循环代谢在肿瘤-基质串扰中的作用仍未明晰。本研究发现，结直肠癌（colorectal cancer, CRC）细胞可通过自身分泌的外泌体介导肿瘤相关成纤维细胞（cancer-associated fibroblasts, CAFs）发生尿素循环代谢重编程。重编程后的肿瘤相关成纤维细胞可通过提供尿素循环代谢产物，尤其是精氨酸（arginine, Arg），促进结直肠癌细胞的生长。因此，精氨酸剥夺会抑制结直肠癌细胞的增殖。进一步研究显示，精氨酸剥夺会增强结直肠癌细胞对腐胺（putrescine, Put）的依赖性，并上调多胺生物合成限速酶鸟氨酸脱羧酶（ornithine decarboxylase, ODC）的表达。联合应用精氨酸剥夺与鸟氨酸脱羧酶抑制剂可有效抑制结直肠癌细胞的生长。本研究阐明了肿瘤相关成纤维细胞与结直肠癌细胞之间的尿素循环代谢互作机制，并证实了精氨酸限制联合鸟氨酸脱羧酶阻断疗法用于结直肠癌治疗的潜在临床价值。整体实验设计：为探究结直肠癌细胞分泌的外泌体对肿瘤相关成纤维细胞的影响，我们对经HCT116细胞分泌的外泌体（HCT116 Exo）处理的原代肿瘤相关成纤维细胞，以及经空白载体处理的对照组细胞进行了RNA测序（RNA sequencing, RNA-seq）。