2. Academic Validation
  3. Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis

Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis

  • Cell Rep. 2022 Mar 8;38(10):110451. doi: 10.1016/j.celrep.2022.110451.
Jun-Long Zhao 1,  Yu-Chen Ye 1,  Chun-Chen Gao 1,  Liang Wang 1,  Kai-Xi Ren 2,  Ru Jiang 3,  Si-Jun Hu 4,  Shi-Qian Liang 1,  Jian Bai 1,  Jia-Long Liang 5,  Peng-Fei Ma 1,  Yi-Yang Hu 1,  Ben-Chang Li 4,  Yong-Zhan Nie 4,  Yan Chen 6,  Xiao-Fei Li 7,  Wei Zhang 3,  Hua Han 8,  Hong-Yan Qin 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an 710032, China.
  • 2 State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an 710032, China; Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, China.
  • 3 School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China.
  • 4 State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China.
  • 5 School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China; The No. 946 Hospital of PLA Land Force, Beijing, China.
  • 6 Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
  • 7 Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, China.
  • 8 State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an 710032, China; State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, China. Electronic address: [email protected].
  • 9 State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an 710032, China. Electronic address: [email protected].
PMID: 35263597 DOI: 10.1016/j.celrep.2022.110451
Abstract

Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) play critical roles in tumorigenesis. However, the mechanisms underlying MDSC and TAM development and function remain unclear. In this study, we find that myeloid-specific activation of Notch/RBP-J signaling downregulates lactate transporter MCT2 transcription via its downstream molecule Hes1, leading to reduced intracellular lactate levels, blunted granulocytic MDSC (G-MDSC) differentiation, and enhanced TAM maturation. We identify c-Jun as a novel intracellular sensor of lactate in myeloid cells using liquid-chromatography-mass spectrometry (LC-MS) followed by CRISPR-Cas9-mediated gene disruption. Meanwhile, lactate interacts with c-Jun to protect from FBW7 ubiquitin-ligase-mediated degradation. Activation of Notch signaling and blockade of lactate import repress tumor progression by remodeling myeloid development. Consistently, the relationship between the Notch-MCT2/lactate-c-Jun axis in myeloid cells and tumorigenesis is also confirmed in clinical lung Cancer biopsies. Taken together, our current study shows that lactate metabolism regulated by activated Notch signaling might participate in MDSC differentiation and TAM maturation.

Keywords

MCT2; MDSC; TAM; c-Jun; lactate; notch signaling.

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