Arginine dependency in omental metastasis of epithelial ovarian cancer reveals a therapeutic vulnerability

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies, and the tumors with advanced-stage are frequently characterized by extensive metastasis. Although metabolic reprogramming of amino acids represents a hallmark of cancer, its specific role in the metastatic progression of EOC remains poorly understood. Here, we identified a critical metabolic vulnerability in omental metastasis of EOC. Despite defective endogenous synthesis, arginine accumulation depends on exogenous uptake. In vivo experiments demonstrated that dietary arginine deprivation suppressed tumor growth and metastasis, whereas supplementation or enhanced uptake of arginine promoted tumor cell proliferation, invasion, and migration in vitro. Mechanistically, increased arginine binds to the RNA helicase DDX3X, inducing nuclear retention of DDX3X and further promoting the transcription of DNA damage response (DDR)-related genes, thereby facilitating DDR through activating the ATM/CHK2/P53 axis to enable cancer cells to survive under metastatic stress. Notably, arginine restriction or pharmacological inhibition of DDX3X did effectively suppress both primary tumor growth and omental metastasis in mouse models. Collectively, our findings reveal that arginine is a metabolic vulnerability in omental metastasis of EOC, indicating that arginine restriction and DDX3X inhibition represent promising therapeutic strategies.