Nasopharyngeal carcinoma (NPC) is one of the common head and neck cancers in Southern China and Southeast Asia. Although current studies have adequately characterized the tumor microenvironment (TME) of NPC, little attention has been paid to how cell-cell interactions within the TME promote tumorigenesis. In this study, it is found that C1q + tumor-associated macrophages (TAMs) are significantly enriched in NPC tumors. Moreover, both enriched C1q + TAMs and elevated C1q expression are associated with the progression and poor prognosis in NPC patients. In vitro and in vivo studies demonstrate that C1q directly boosts the malignancy and stemness of tumor cells. Mechanistically, C1q activates the Phosphatidylinositol-3-kinase (PI3K)/AKT pathway through interacting with GPR17, a member of the G protein-coupled receptor family, thereby inducing DNA hypermethylation of tumor cells to promote tumor development. It is further proved that DNA hypermethylated NPC cells induced by C1q elicited the immunosuppressive phenotype of TAMs. Targeted blockade of C1q with a neutralizing antibody restricts NPC progression in the humanized mouse model. It is assumed that the differentiation of C1q + TAMs possibly acquired both M1 and M2 polarization conditions. These findings provide new insights into the cellular communication in the TME of NPC and may have important applications for the development of new targeted therapies.
Anxiety disorders are one of the most epidemic and chronic psychiatric disorders. An incomplete understanding of anxiety pathophysiology has limited the development of highly effective drugs against these disorders. GPR17 has been shown to be involved in multiple sclerosis and some acute brain injury disorders. However, no study has investigated the role of GPR17 in psychiatric disorders. In a well-established chronic restraint stress (CRS) mouse model, using a combination of pharmacological and molecular biology techniques, viral tracing, in vitro electrophysiology recordings, in vivo fiber photometry, chemogenetic manipulations and behavioral tests, we demonstrated that CRS induced anxiety-like behaviors and increased the expression of GPR17 in basolateral amygdala (BLA) glutamatergic neurons. Inhibition of GPR17 by cangrelor or knockdown of GPR17 by adeno-associated virus in BLA glutamatergic neurons effectively improved anxiety-like behaviors. Overexpression of GPR17 in BLA glutamatergic neurons increased the susceptibility to anxiety-like behaviors. What's more, BLA glutamatergic neuronal activity was required for anxiolytic-like effects of GPR17 antagonist and GPR17 modulated anxiety-like behaviors via BLA to ventral hippocampal CA1 glutamatergic projection. Our study finds for the first and highlights the new role of GPR17 in regulating anxiety-like behaviors and it might be a novel potential target for therapy of anxiety disorders.
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