Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis
Jun-Long Zhao,
Yu-Chen Ye,
Chun-Chen Gao,
Liang Wang,
Kai-Xi Ren,
Ru Jiang,
Si-Jun Hu,
Shi-Qian Liang,
Jian Bai,
Jia-Long Liang,
Peng-Fei Ma,
Yi-Yang Hu,
Ben-Chang Li,
Yong-Zhan Nie,
Yan Chen,
Xiao-Fei Li,
Wei Zhang,
Hua Han,
Hong-Yan Qin
Affiliations
Jun-Long Zhao
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
Yu-Chen Ye
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
Chun-Chen Gao
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
Liang Wang
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
Kai-Xi Ren
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
Ru Jiang
School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
Si-Jun Hu
State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China
Shi-Qian Liang
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
Jian Bai
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
Jia-Long Liang
School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China; The No. 946 Hospital of PLA Land Force, Beijing, China
Peng-Fei Ma
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
Yi-Yang Hu
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
Ben-Chang Li
State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China
Yong-Zhan Nie
State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China
Yan Chen
Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
Xiao-Fei Li
Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, China
Wei Zhang
School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
Hua Han
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; Corresponding author
Hong-Yan Qin
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; Corresponding author
Summary: 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.
