Multi-omics analysis revealed the addiction to glutamine and susceptibility to de novo lipogenesis of endometrial neoplasm.

The endometrium is a proliferative tissue controlled by the menstrual cycle. Endometrial hyperplasia (EH) is a type of neoplastic disease that may develop into endometrial hyperplasia with atypia (EHA) or endometrial adenocarcinoma (EA). We performed a multi-omics analysis of a collection of endometrial tissues with four different proliferative statuses from two independent cohorts of patients. A positive association between the level of glutamine and malignancy, as well as addiction of EHA/EA neoplasms to glutamine, was identified. Further investigation revealed the dual mechanism by which glutamine influences the development of endometrial neoplasms. On one hand, glutamine regulates the level of c-MYC by controlling its translational process. On the other hand, glutamine is a major source of energy for endometrial neoplasms. Reprogramming the glutamine metabolism towards de novo lipogenesis affects the growth of endometrial adenocarcinoma in vitro, ex vivo and in vivo. Our study revealed the importance of maintaining metabolic homeostasis in endometrial tissues. The enhancement of de novo lipogenesis is a promising therapeutic strategy for treating endometrial adenocarcinoma.