PMID- 36324684
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221104
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 13
DP  - 2022
TI  - Sphingomyelin synthase 2 is a positive regulator of the CSF1R-STAT3 pathway in 
      pancreatic cancer-associated macrophage.
PG  - 902016
LID - 10.3389/fphar.2022.902016 [doi]
LID - 902016
AB  - Background: Tumor-associated macrophages (TAMs) are one of the most abundant 
      immune cells in the pancreatic cancer stroma and are related to the poor 
      prognosis of pancreatic ductal adenocarcinoma (PDAC) patients. Therefore, 
      targeting tumor-associated macrophages is a possible strategy for the treatment 
      of pancreatic cancer. Purpose: We would like to investigate the role of 
      sphingomyelin synthase 2 (SMS2) and the effect of the synthase 2 selective 
      inhibitor YE2 in TAMs and the pancreatic tumor microenvironment. In addition, we 
      also would like to investigate the mechanism by which YE2 attenuates macrophage 
      M2 polarization. Methods: YE2 was utilized to treat macrophages (in vitro) and 
      mice (in vivo). Western blotting and real-time PCR were used to detect the 
      protein levels and mRNA levels of macrophage M2 polarization markers and their 
      downstream signaling pathways. Sphingomyelin synthase 2 gene knockout (KO) mice 
      and their controls were used to establish a PANC-02 orthotopic pancreatic cancer 
      model, and immune cell infiltration in the tumor tissue was analyzed by 
      immunohistochemistry (IHC). Results: We found that sphingomyelin synthase 2 mRNA 
      expression is positively correlated with tumor-associated macrophages, the 
      immunosuppressive microenvironment, and poor prognosis in pancreatic ductal 
      adenocarcinoma patients. Sphingomyelin synthase 2 deficiency was confirmed to 
      have an inhibitory effect on the growth of orthotopic PANC-02 tumors in vivo. The 
      deficiency not only reduced the infiltration of tumor-associated macrophages but 
      also regulated other immune components in the tumor microenvironment. In tissue 
      culture, YE2 inhibited M2 polarization in both bone marrow-derived macrophages 
      (BMDMs) and THP-1 macrophages and eliminated the protumor effect of M2 
      macrophages. In the mouse model, YE2 treatment reduced the infiltration of TAMs 
      and regulated other immune components in the tumor microenvironment, slowing the 
      progression of PANC-02 tumors. In terms of mechanism, we found that the 
      inhibition of sphingomyelin synthase 2 could downregulate the expression of IL4Ralpha 
      and CSF1R, thereby attenuating M2 polarization. Conclusion: The sphingomyelin 
      synthase 2 inhibitor YE2 or sphingomyelin synthase 2 deficiency can prevent 
      macrophage M2 polarization in pancreatic cancer, and sphingomyelin synthase 2 
      could be a new potential target for the treatment of pancreatic cancer.
CI  - Copyright (c) 2022 He, Gu, Yang, Xu, Hu, Wang, Huang, Lou, Ding, Zhou, Ye, Yu and 
      Dong.
FAU - He, Shuhua
AU  - He S
AD  - Department of Pharmacology and Biochemistry, School of Pharmacy, Fudan 
      University, Shanghai, China.
FAU - Gu, Xiang
AU  - Gu X
AD  - Department of Pharmacology and Biochemistry, School of Pharmacy, Fudan 
      University, Shanghai, China.
FAU - Yang, Jintong
AU  - Yang J
AD  - Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 
      Shanghai, China.
FAU - Xu, Fei
AU  - Xu F
AD  - Department of Pharmacology and Biochemistry, School of Pharmacy, Fudan 
      University, Shanghai, China.
FAU - Hu, Jiachun
AU  - Hu J
AD  - Department of Pharmacology and Biochemistry, School of Pharmacy, Fudan 
      University, Shanghai, China.
FAU - Wang, Wei
AU  - Wang W
AD  - Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 
      Shanghai, China.
FAU - Huang, Yiheng
AU  - Huang Y
AD  - Department of Clinical Medicine, Shanghai Jiaotong University of Medicine, 
      Shanghai, China.
FAU - Lou, Bin
AU  - Lou B
AD  - Department of Pharmacology and Biochemistry, School of Pharmacy, Fudan 
      University, Shanghai, China.
FAU - Ding, Tingbo
AU  - Ding T
AD  - Experiment & Teaching Center, School of Pharmacy, Fudan University, Shanghai, 
      China.
FAU - Zhou, Lu
AU  - Zhou L
AD  - Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 
      Shanghai, China.
FAU - Ye, Deyong
AU  - Ye D
AD  - Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 
      Shanghai, China.
FAU - Yu, Ker
AU  - Yu K
AD  - Department of Pharmacology and Biochemistry, School of Pharmacy, Fudan 
      University, Shanghai, China.
FAU - Dong, Jibin
AU  - Dong J
AD  - Department of Pharmacology and Biochemistry, School of Pharmacy, Fudan 
      University, Shanghai, China.
AD  - Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, 
      Shanghai, China.
LA  - eng
PT  - Journal Article
DEP - 20221017
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC9618885
OTO - NOTNLM
OT  - M2-like macrophages
OT  - pancreatic ductal adenocarcinoma
OT  - sphingomyelin synthase 2
OT  - sphingomyelin synthase 2 inhibitor YE2
OT  - tumor microenvironment
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/11/04 06:00
MHDA- 2022/11/04 06:01
PMCR- 2022/10/17
CRDT- 2022/11/03 02:32
PHST- 2022/03/22 00:00 [received]
PHST- 2022/09/22 00:00 [accepted]
PHST- 2022/11/03 02:32 [entrez]
PHST- 2022/11/04 06:00 [pubmed]
PHST- 2022/11/04 06:01 [medline]
PHST- 2022/10/17 00:00 [pmc-release]
AID - 902016 [pii]
AID - 10.3389/fphar.2022.902016 [doi]
PST - epublish
SO  - Front Pharmacol. 2022 Oct 17;13:902016. doi: 10.3389/fphar.2022.902016. 
      eCollection 2022.