FAM50A drives breast cancer brain metastasis through interaction with C9ORF78 to enhance ʟ-asparagine production

Elevated levels of asparagine, catalyzed by asparagine synthetase (ASNS), have been identified as a prerequisite for lung metastasis in breast cancer. However, the roles and regulatory mechanisms of ASNS in breast cancer brain metastasis (BCBM) are not well understood. Our study revealed that the family with sequence similarity 50 member A (FAM50A) gene substantially modulates the brain metastatic potential of breast cancer by up-regulating ASNS and promoting asparagine biosynthesis. We demonstrated that FAM50A forms a complex with chromosome 9 open reading frame 78 (C9ORF78), specifically at the S121 residue, to enhance ASNS transcription. This interaction accelerates the rate of ASNS-mediated asparagine synthesis, which is essential in facilitating metastatic cascades to the brain. From a therapeutic perspective, both the genetic suppression of FAM50A and pharmacological inhibition of asparagine synthesis effectively counteract BCBM. Our results highlight the importance of the FAM50A-ASNS signaling pathway in BCBM therapy.