Dear Editor:Uveal melanoma(UM)is a deadly ocular cancer highly metastasizing to the liver.1 The vascular barrier in the eyes is critical in preventing UM metastasis.However,the mechanism by which melanoma escapes from...Dear Editor:Uveal melanoma(UM)is a deadly ocular cancer highly metastasizing to the liver.1 The vascular barrier in the eyes is critical in preventing UM metastasis.However,the mechanism by which melanoma escapes from the eyes is mainly unknown.Metastatic UM tumors are highly vascularized with leaky blood vessels due to excessive vascular endothelial growth factor(VEGF)production.2 Here,we discovered that UM cells with commonly found mutations(GNA11Q209L or GNAQQ209L)rely on VEGF to permeabilize the endothelial barrier and promote UM cell migration across the endothelium.展开更多
Proliferative diabetic retinopathy(PDR)is a major complication of diabetes characterized by pathological angiogenesis in the retina.Standard treatment includes vitrectomy to remove these abnormal vessels,and the resul...Proliferative diabetic retinopathy(PDR)is a major complication of diabetes characterized by pathological angiogenesis in the retina.Standard treatment includes vitrectomy to remove these abnormal vessels,and the resulting clinical specimens provide an opportunity to define drivers of PDR.Here,we profiled endothelial and immune cells from such samples to identify disease mechanisms.In some patients,endothelial cells were more abundant,whereas in others,immune cells predominated.Immune cells exhibited gene expression programs directed against pathological endothelium,suggesting an endogenous defense that may explain the scarcity of endothelial cells in certain cases.Preoperative anti-vascular endothelial growth factor(VEGF)therapy altered transcriptional programs in both endothelial and immune cells,indicating that its effects extend beyond the vasculature.A comparison of endothelial signatures from PDR patients and nondiabetic donor retinas revealed a distinct molecular program in PDR,prominently marked by mitochondrial dysfunction.In contrast,endothelial cells from the murine oxygen-induced retinopathy(OIR)model lacked mitochondrial dysfunction,although other features of pathological angiogenesis were shared.These findings suggest that PDR is not a uniform disease but comprises distinct types characterized by either immune-mediated clearance of pathological vessels or endothelial mitochondrial dysfunction.They also revealed that anti-VEGF therapy influences both endothelial and immune compartments,with implications for treatment strategies.Finally,the data clarify both the relevance and limitations of the OIR model for preclinical testing of new therapeutic targets.展开更多
基金supported by grants from the American Cancer Society Discovery Boost Grants(AHEAD-DBG-23-1156429-01-MM to KHY)National Institute of Health(NIH)(R01EY029339 to KHY,K12EY021475 and K08EY034935 to DEM,and P30EY001792 to the Department of Ophthalmology&Visual Sciences).
文摘Dear Editor:Uveal melanoma(UM)is a deadly ocular cancer highly metastasizing to the liver.1 The vascular barrier in the eyes is critical in preventing UM metastasis.However,the mechanism by which melanoma escapes from the eyes is mainly unknown.Metastatic UM tumors are highly vascularized with leaky blood vessels due to excessive vascular endothelial growth factor(VEGF)production.2 Here,we discovered that UM cells with commonly found mutations(GNA11Q209L or GNAQQ209L)rely on VEGF to permeabilize the endothelial barrier and promote UM cell migration across the endothelium.
基金funded by the National Institute of Health grants EY031350(M.A.M.,B.B.,Y.L.,A.K.),EY001792(M.A.M.,B.B.,Y.L.,A.K.),and T32 HL144459(M.A.M.)Additional funding was provided by an Illinois Society to Prevent Blindness grant(M.A.M.,B.B.,Y.L.,P.R.)+1 种基金a Retina Research Foundation grant(A.K.)an unrestricted grant from the Research to Prevent Blindness Foundation(M.A.M.,B.B.,Y.L.,P.R.,N.S.,J.I.L.,W.F.M.,F.Y.C.,L.J.U.,R.V.P.C.,M.M.,R.A.H.,C.B.,A.O.,S.D.,B.S.,R.C.,Y.I.L.,M.J.H.,A.K.)。
文摘Proliferative diabetic retinopathy(PDR)is a major complication of diabetes characterized by pathological angiogenesis in the retina.Standard treatment includes vitrectomy to remove these abnormal vessels,and the resulting clinical specimens provide an opportunity to define drivers of PDR.Here,we profiled endothelial and immune cells from such samples to identify disease mechanisms.In some patients,endothelial cells were more abundant,whereas in others,immune cells predominated.Immune cells exhibited gene expression programs directed against pathological endothelium,suggesting an endogenous defense that may explain the scarcity of endothelial cells in certain cases.Preoperative anti-vascular endothelial growth factor(VEGF)therapy altered transcriptional programs in both endothelial and immune cells,indicating that its effects extend beyond the vasculature.A comparison of endothelial signatures from PDR patients and nondiabetic donor retinas revealed a distinct molecular program in PDR,prominently marked by mitochondrial dysfunction.In contrast,endothelial cells from the murine oxygen-induced retinopathy(OIR)model lacked mitochondrial dysfunction,although other features of pathological angiogenesis were shared.These findings suggest that PDR is not a uniform disease but comprises distinct types characterized by either immune-mediated clearance of pathological vessels or endothelial mitochondrial dysfunction.They also revealed that anti-VEGF therapy influences both endothelial and immune compartments,with implications for treatment strategies.Finally,the data clarify both the relevance and limitations of the OIR model for preclinical testing of new therapeutic targets.
