Establishment of immunocompetent spontaneous glioma model to study glioma-associated astrocytes

星形胶质细胞在大脑中发挥着重要的生理功能。然而，在回应中却五花八门

Astrocytes play critical physiological functions in the brain. However, in response to diverse insults, astrocytes become reactive and help to restore homeostasis. Their responses can also turn pathological as observed in chronic inflammation and brain tumors. Reactive astrocytes (RA) and their responses have recently been recognized as key players in the microenvironment of both primary and metastatic brain tumors. Recently a subset of RA with activated STAT3 has been shown to be critical for supporting growth of both brain metastatic lesions as well as glioblastoma cells (GBM). Although activation of STAT3 in RA supports the growth of GBM cells, mechanisms that drive STAT3 activation in RA remain elusive. While a plethora of cytokines and growth factors induce temporal STAT3 activation, a bioactive sphingolipid, sphingosine-1- phosphate (S1P) can drive persistent activation of STAT3 via its G-protein-coupled receptor 1 (S1PR1). S1PR1 is highly expressed by astrocytes, and deletion of S1PR1 in astrocytes limits their reactivity, while sphingosine kinase 1 generating S1P is overexpressed in GBM. These findings raise a possibility that GBM-derived S1P activates STAT3 in RA via the S1P/S1PR1/STAT3 axis. Nevertheless, the major obstacle in studying the mechanisms of RA activation is the lack of appropriate glioma model that would allow genetic manipulation specifically in these cells. We have recently further developed a previously established spontaneous mouse glioma model, which will allow us to test the importance of genes in RA. We will examine the usefulness of our model to study RA, and test whether the S1P/S1PR1/STAT3 axis drives gene expression programs that re-wire RA leading to establishment of an immunosuppressive state. We will also determine whether S1PR1 inhibition affects preestablished gliomas.