Tumor cell-derived N-acetyl-aspartyl-glutamate reshapes the tumor microenvironment to facilitate breast cancer metastasis

  • Sci Bull (Beijing). 2024 Dec 27:S2095-9273(24)00949-6. doi: 10.1016/j.scib.2024.12.039.
Jie Xia  1 ,  Lixing Zhang  2 ,  Wucheng Zhu  3 ,  Juchuanli Tu  3 ,  Xilei Peng  3 ,  Qiaodan Deng  3 ,  Siqin Li  3 ,  Xueyan He  3 ,  Haonan Dong  3 ,  Cuicui Liu  4 ,  Xian Chen  3 ,  Jiahui Xu  3 ,  Wei Ma  3 ,  Yi Xiao  5 ,  Wen Liu  6 ,  Guohong Hu  7 ,  Yi-Zhou Jiang  5 ,  Ceshi Chen  8 ,  Xiu-Wu Bian  9 ,  Zhi-Ming Shao  5 ,  Suling Liu  10
Affiliations
  • 1. Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Department of Oncology; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai 200032, China; Jinfeng Laboratory, Chongqing 401329, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.
  • 2. Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Department of Oncology; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai 200032, China; Jinfeng Laboratory, Chongqing 401329, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: [email protected].
  • 3. Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Department of Oncology; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai 200032, China.
  • 4. Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 5. Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Precision Cancer Medical Center, Fudan University Shanghai Cancer Center, Shanghai 201315, China.
  • 6. School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
  • 7. Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
  • 8. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming 650201, China; Academy of Biomedical Engineering & The Third Affiliated Hospital, Kunming Medical University, Kunming 650500, China.
  • 9. Jinfeng Laboratory, Chongqing 401329, China; Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.
  • 10. Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Department of Oncology; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai 200032, China; Jinfeng Laboratory, Chongqing 401329, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: [email protected].
PMID: 39800628 DOI: 10.1016/j.scib.2024.12.039
Abstract

Neurotransmitters are increasingly recognized to play important roles in limiting anti-tumor immunity. N-acetyl-aspartyl-glutamate (NAAG) has been extensively studied in neurological disorders; however, its potential role in restricting anti-tumor immunity has not been investigated. Here, we demonstrated that NAAG or its synthetase RimK-like family member B (RIMKLB) significantly disrupted anti-tumor immunity by rewiring the myeloid progenitor differentiation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which in turn promoted breast Cancer growth and metastasis. Mechanistically, NAAG sustained the tumor immunosuppressive microenvironment by activating an NR2B-containing NMDA Receptor (NR2B-NMDAR)-dependent p38-NOTCH1 axis, and subsequently stimulating tumor cell migration and invasion, as well as inducing PMN-MDSC differentiation and expansion. In mouse models, RIMKLB ablation or NMDAR inhibition enhanced the efficacy of anti-PD-1 therapy and suppressed tumor progression. An analysis of clinical samples revealed that high levels of NAAG and NR2B-NMDAR predicted a poor prognosis in TNBC patients. Collectively, our findings have uncovered a signaling role for tumor-derived NAAG beyond its classic function as a neurotransmitter that can be targeted pharmacologically to enhance immunotherapy against breast Cancer.

Keywords
Breast cancer metastasis; NAAG; NMDAR; PMN-MDSC; RIMKLB.
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