Abstract 5375: Sex-specific differences in response to exogenous asparagine supplementation during colorectal tumor growth is dependent on aromatase activity

Studies have shown that sex-related differences in asparagine metabolism are associated with gastrointestinal diseases prognosis. However, the effects of exogenous asparagine on the incidence and phenotype of colorectal cancer (CRC) in both men and women remain unclear. This study describes the relationship between exogenous asparagine supplementation and estradiol secretion which is critical for understanding mechanisms of sex-dependent signaling events. We show that asparagine supplementation causes pronounced sex-dependent alteration in cancer metabolomics using in vivo and in vitro approaches. We intraperitoneally administered asparagine to tumor-bearing immunodeficient male and female Rag2/Il2RG (R2G2) mice, at doses of 1 mg/kg and 10 mg/kg body weight. Asparagine supplementation causes a significant increase in cellular asparagine levels in the tumor-bearing male and female R2G2 mice but increases serum estradiol levels and suppresses tumor growth in females R2G2 mice only. Additionally, we combined transcriptome, metabolome and immunochemical analyses and found that asparagine treatment induces intra-tumoral metabolic changes in colorectal cancer cells based on biological sex. We established that in females only, exogenous asparagine exerts a negative feed-back effect on de novo asparagine synthesis and activates a sub-population of macrophages that secretes estradiol via a Cytochrome P450 Family 19 (CYP19)-dependent mechanism, resulting in improved tumor-specific survival. Conversely, in the male mice, asparagine treatment augments tumor growth by decreasing the number of tumor-associated macrophages and reduces CYP19-mediated estradiol secretion leading to worsened tumor-specific survival. Overall, our results revealed a novel role for exogenous asparagine supply during cancer progression and underscores the importance of understanding mechanisms that control asparagine biosynthesis, especially for patients with CRC. Citation Format: Oladimeji Aladelokun, Katherine Benitez, Yuying Wang, Abhishek Jain, Domenica Berardi, Georgio Maroun, Xinyi Shen, Jatin Roper, Joanna Gibson, Kaelyn Sumigray, Sajid A. Khan, Caroline H. Johnson. Sex-specific differences in response to exogenous asparagine supplementation during colorectal tumor growth is dependent on aromatase activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5375.