Sex-specific effects of exogenous asparagine on colorectal tumor growth, 17β-estradiol levels, and aromatase

Sex-related differences in asparagine metabolism are associated with cancer prognosis. However, the effect of exogenous asparagine on colorectal cancer (CRC) growth in men and women remain unclear. This study aims to understand the relationship between exogenous asparagine supplementation and 17β-estradiol levels and to elucidate mechanisms underlying sex-dependent signaling during CRC development. We administered asparagine intraperitoneally to tumor-bearing immunodeficient male and female Rag2/Il2RG (R2G2) mice. Asparagine supplementation caused a significant increase in tumor asparagine levels in both the tumor-bearing male and female R2G2 mice but increased serum estradiol levels and suppressed tumor growth in female R2G2 mice only. Additionally, we combined transcriptome, metabolome and immunochemical analyses and found that intraperitoneal asparagine treatment induced sex-dependent intra-tumoral metabolic changes to asparagine, aspartate, glutamine and glutamate levels in CRC cells. We observed that in females, exogenous asparagine exerts a negative feed-back effect on de novo asparagine synthesis and is associated with the activation of a sub-population of macrophages that may secrete 17β-estradiol via an aromatase or cytochrome P450 family 19 (CYP19)-dependent mechanism, resulting in improved tumor-specific survival. Conversely, in male mice, asparagine treatment augments tumor growth and is related to decreased numbers of macrophages, reduction in CYP19-mediated 17β-estradiol secretion leading to worsened tumor-specific survival. Overall, our results reveal a novel and sex-specific role for exogenous asparagine during cancer progression and underscores the importance of understanding mechanisms that control asparagine biosynthesis.