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

  • Sci Adv. 2025 Jun 20;11(25):eadt3075. doi: 10.1126/sciadv.adt3075.
Weilong Chen  1 ,  Yuanyuan Qin  1 ,  Libo Qiao  1 ,  Xue Liu  1 ,  Chenyun Gao  1 ,  Tian-Ran Li  2 ,  Yanrui Luo  3 ,  Dongxue Li  1  4 ,  Hong Yan  1  5 ,  Linhong Han  1  2 ,  Long Hai  1  4 ,  Fang Nie  6 ,  Hai-Bo Wu  1 ,  Cong Chen  2 ,  Yi-Fang Ping  2  3 ,  Xiu-Wu Bian  1  2  3
Affiliations
  • 1. Department of Pathology and Intelligent Pathology Institute, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
  • 2. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China.
  • 3. Jinfeng Laboratory, Chongqing 400039, China.
  • 4. Department of Neurosurgery, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 5. Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
  • 6. Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging and Interventional Radiology, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China.
PMID: 40531994 DOI: 10.1126/sciadv.adt3075
Abstract

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.

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