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2018
Zhang T, Li J, He Y, et al. A small molecule targeting myoferlin exerts promising anti-tumor effects on breast cancer[J]. Nature Communications, 2018, 9(1).
Breast cancer is one of the most lethal cancers in women when it reaches the metastatic stage. Here, we screen a library of small molecules for inhibitors of breast cancer cell invasion, and use structure/activity relationship studies to develop a series of small molecules with improved activity. We find WJ460 as one of the lead compounds exerting anti-metastatic activity in the nanomolar range in breast cancer cells. Proteomic and biochemical studies identify myoferlin (MYOF) as the direct target of WJ460. In parallel, loss of MYOF or pharmacological inhibition of MYOF by WJ460 reduces breast cancer extravasation into the lung parenchyma in an experimental metastasis mouse model, which reveals an essential role of MYOF in breast cancer progression. Our findings suggest that MYOF can be explored as a molecular target in breast cancer metastasis and that targeting MYOF by WJ460 may be a promising therapeutic strategy in MYOF-driven cancers.
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2018
Huang H., Xiong Q., Wang N., et al. Kisspeptin/GPR54 signaling restricts antiviral innate immune response through regulating calcineurin phosphatase activity. Sci. Adv. (2018).
G protein–coupled receptor 54 (GPR54), the key receptor for the neuropeptide hormone kisspeptin, plays essential roles in regulating puberty development and cancer metastasis. However, its role in the antiviral innate immune response is unknown. We report that virus-induced type I interferon (IFN-I) production was significantly enhanced in Gpr54-deficient cells and mice and resulted in restricted viral replication. We found a marked increase of kisspeptin in mouse serum during viral infection, which, in turn, impaired IFN-I production and antiviral immunity through the GPR54/calcineurin axis. Mechanistically, kisspeptin/GPR54 signaling recruited calcineurin and increased its phosphatase activity to dephosphorylate and deactivate TANK [tumor necrosis factor receptorassociated factor (TRAF) family member-associated NF-κB activator]–binding kinase 1 (TBK1) in a Ca2+-dependent manner. Thus, our data reveal a kisspeptin/GPR54/calcineurin-mediated immune evasion pathway exploited by virus through the negative feedback loop of TBK1 signaling. These findings also provide insights into the function and cross-talk of kisspeptin, a known neuropeptide hormone, in antiviral innate immune response.
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2018
Yang L., Zhang X., Wang L., et al. Increasing targeting scope of adenosine base editors in mouse and rat embryos through fusion of TadA deaminase with Cas9 variants. Protein Cell (2018).
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2018
Tan B., Shi X., Zhang J., Qin J., et al. Inhibition of Rspo-Lgr4 Facilitates Checkpoint Blockade Therapy by Switching Macrophage Polarization. Cancer Research (2018).
Therapies targeting immune checkpoints have shown great clinical potential in a subset of patients with cancer but may be hampered by a failure to reverse the immunosuppressive tumor microenvironment(TME). As the most abundant immune cells in TME, tumor-associated macrophages(TAM) play nonredundant roles in restricting antitumor immunity. The leucine-rich repeat-containing G-protein–coupled receptor 4 (Lgr4, also known as Gpr48) has been associated with multiple physiologic and pathologic functions. Lgr4 and its ligands R-spondin 1–4 have been shown to promote the growth and metastasis of tumor cells. However, whether Lgr4 can promote tumor progression by regulating the function of immune cells in the tumor micro-environment remains largely unknown. Here, we demonstrate that Lgr4 promotes macrophage M2 polarization through Rspo/Lgr4/Erk/Stat3 signaling. Notably, urethane-induced lung carcinogenesis, Lewis lung carcinoma (LLC), and B16F10 melanoma tumors were all markedly reduced in Lgr4fl/flLyz2cre/+ mice, characterized by fewer protumoral M2 TAMs and increased CD8+ T lymphocyte infiltration in the TME. Furthermore, LLC tumor growth was greatly depressed when Rspo/Lgr4/Erk/Stat3 signaling was blocked with either the LGR4 extracellular domain or an anti-Rspo1 antibody. Importantly, blocking Rspo-Lgr4 signaling overcame LLC resistance to anti-PD-1 therapy and improved the efficacy of PD-1 immunotherapy against B16F10 melanoma, indicating vital roles of Rspo-Lgr4 in host antitumor immunity and a potential therapeutic target in cancer immunotherapy.
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2018
Wang T., Cui X., Xie L., et al. Kisspeptin Receptor GPR54 Promotes Adipocyte Differentiation and Fat Accumulation in Mice. Frontiers in Physiology (2018).
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2018
Shao Y., Wang L., Guo N., et al. Cas9-nickase–mediated genome editing corrects hereditary tyrosinemia in rats. J. Biol. Chem. (2018).
