Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis
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 do...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-03-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124722001784 |
| _version_ | 1819349522257543168 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jun-Long Zhao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-24T19:01:51Z |
| format | Article |
| id | doaj.art-692f4f3e0a434d6e9248d6015643b4d7 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-24T19:01:51Z |
| publishDate | 2022-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-692f4f3e0a434d6e9248d6015643b4d72022-12-21T16:43:11ZengElsevierCell Reports2211-12472022-03-013810110451Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axisJun-Long Zhao0Yu-Chen Ye1Chun-Chen Gao2Liang Wang3Kai-Xi Ren4Ru Jiang5Si-Jun Hu6Shi-Qian Liang7Jian Bai8Jia-Long Liang9Peng-Fei Ma10Yi-Yang Hu11Ben-Chang Li12Yong-Zhan Nie13Yan Chen14Xiao-Fei Li15Wei Zhang16Hua Han17Hong-Yan Qin18State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an 710032, ChinaState Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an 710032, ChinaState Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an 710032, ChinaState Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an 710032, ChinaState 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, ChinaSchool of Pharmacy, Fourth Military Medical University, Xi'an 710032, ChinaState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, ChinaState Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an 710032, ChinaState Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an 710032, ChinaSchool of Pharmacy, Fourth Military Medical University, Xi'an 710032, China; The No. 946 Hospital of PLA Land Force, Beijing, ChinaState Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an 710032, ChinaState Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an 710032, ChinaState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, ChinaState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, ChinaDepartment of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, ChinaDepartment of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, ChinaSchool of Pharmacy, Fourth Military Medical University, Xi'an 710032, ChinaState 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 authorState 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124722001784notch signalingMDSCTAMlactateMCT2c-Jun |
| spellingShingle | 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 Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis Cell Reports notch signaling MDSC TAM lactate MCT2 c-Jun |
| title | Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis |
| title_full | Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis |
| title_fullStr | Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis |
| title_full_unstemmed | Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis |
| title_short | Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis |
| title_sort | notch mediated lactate metabolism regulates mdsc development through the hes1 mct2 c jun axis |
| topic | notch signaling MDSC TAM lactate MCT2 c-Jun |
| url | http://www.sciencedirect.com/science/article/pii/S2211124722001784 |
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