TY - JOUR
T1 - PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model
AU - Wang, Tong
AU - Jing, Bo
AU - Xu, Dongliang
AU - Liao, Yueling
AU - Song, Hongyong
AU - Sun, Beibei
AU - Guo, Wenzheng
AU - Xu, Jianhua
AU - Li, Kaimi
AU - Hu, Min
AU - Liu, Shuli
AU - Ling, Jing
AU - Kuang, Yanbin
AU - Zhang, Tuo
AU - Zhang, Siwei
AU - Yao, Feng
AU - Zhou, Binhua P.
AU - Deng, Jiong
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/4/9
Y1 - 2020/4/9
N2 - Chronic inflammation has been linked to promotion of tumorigenesis and metastasis in lung. However, due to lack of a relevant animal model for characterization, the underlying mechanism remains elusive. Lung tumor suppressor gene Gprc5a-knockout (ko) mice are susceptible to lung inflammation, tumorigenesis and metastasis, which resembles the pathological features in human patients. Here, we showed that PTGES/PGE2 signaling was highly associated with lung tumorigenesis and metastasis in Gprc5a-ko mice. Interestingly, Ptges-knockout in mouse lung tumor cells, although reduced their stemness and EMT-like features, still formed tumors and lung metastasis in immune-deficient nude mice, but not in immune-competent mice. This suggests that the major role of PTGES/PGE2 signaling in tumorigenicity and lung metastasis is through immunosuppression. Mechanistically, PTGES/PGE2 signaling intrinsically endows tumor cells resistant to T-cell cytotoxicity, and induces cytokines extrinsically for MDSC recruitment, which is crucial for suppression of T-cell immunity. Importantly, targeting PGE2 signaling in Gprc5a-ko mice by PTGES inhibitor suppressed MDSC recruitment, restored T cells, and significantly repressed lung metastasis. Thus, PTGES/PGE2 signaling links immunosuppression and metastasis in an inflammatory lung microenvironment of Gprc5a-ko mouse model.
AB - Chronic inflammation has been linked to promotion of tumorigenesis and metastasis in lung. However, due to lack of a relevant animal model for characterization, the underlying mechanism remains elusive. Lung tumor suppressor gene Gprc5a-knockout (ko) mice are susceptible to lung inflammation, tumorigenesis and metastasis, which resembles the pathological features in human patients. Here, we showed that PTGES/PGE2 signaling was highly associated with lung tumorigenesis and metastasis in Gprc5a-ko mice. Interestingly, Ptges-knockout in mouse lung tumor cells, although reduced their stemness and EMT-like features, still formed tumors and lung metastasis in immune-deficient nude mice, but not in immune-competent mice. This suggests that the major role of PTGES/PGE2 signaling in tumorigenicity and lung metastasis is through immunosuppression. Mechanistically, PTGES/PGE2 signaling intrinsically endows tumor cells resistant to T-cell cytotoxicity, and induces cytokines extrinsically for MDSC recruitment, which is crucial for suppression of T-cell immunity. Importantly, targeting PGE2 signaling in Gprc5a-ko mice by PTGES inhibitor suppressed MDSC recruitment, restored T cells, and significantly repressed lung metastasis. Thus, PTGES/PGE2 signaling links immunosuppression and metastasis in an inflammatory lung microenvironment of Gprc5a-ko mouse model.
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U2 - 10.1038/s41388-020-1207-6
DO - 10.1038/s41388-020-1207-6
M3 - Article
C2 - 32060421
AN - SCOPUS:85079413832
SN - 0950-9232
VL - 39
SP - 3179
EP - 3194
JO - Oncogene
JF - Oncogene
IS - 15
ER -