title: c-Met-mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma.
abstract: Aberrant vascularization is a hallmark of cancer progression and treatment resistance. Here, we have shown that endothelial cell (EC) plasticity drives aberrant vascularization and chemoresistance in glioblastoma multiforme (GBM). By utilizing human patient specimens, as well as allograft and genetic murine GBM models, we revealed that a robust endothelial plasticity in GBM allows acquisition of fibroblast transformation (also known as endothelial mesenchymal transition [Endo-MT]), which is characterized by EC expression of fibroblast markers, and determined that a prominent population of GBM-associated fibroblast-like cells have EC origin. Tumor ECs acquired the mesenchymal gene signature without the loss of EC functions, leading to enhanced cell proliferation and migration, as well as vessel permeability. Furthermore, we identified a c-Met/ETS-1/matrix metalloproteinase-14 (MMP-14) axis that controls VE-cadherin degradation, Endo-MT, and vascular abnormality. Pharmacological c-Met inhibition induced vessel normalization in patient tumor-derived ECs. Finally, EC-specific KO of Met inhibited vascular transformation, normalized blood vessels, and reduced intratumoral hypoxia, culminating in suppressed tumor growth and prolonged survival in GBM-bearing mice after temozolomide treatment. Together, these findings illustrate a mechanism that controls aberrant tumor vascularization and suggest that targeting Endo-MT may offer selective and efficient strategies for antivascular and vessel normalization therapies in GBM, and possibly other malignant tumors.
authors.forename: Menggui
authors.initials: M
authors.lastname: Huang
authors.forename: Tianrun
authors.initials: T
authors.lastname: Liu
authors.forename: Peihong
authors.initials: P
authors.lastname: Ma
authors.forename: R Alan
authors.initials: RA
authors.lastname: Mitteer
authors.forename: Zhenting
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hyun Jun
authors.initials: HJ
authors.lastname: Kim
authors.forename: Eujin
authors.initials: E
authors.lastname: Yeo
authors.forename: Duo
authors.initials: D
authors.lastname: Zhang
authors.forename: Peiqiang
authors.initials: P
authors.lastname: Cai
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Botao
authors.initials: B
authors.lastname: Zhao
authors.forename: Laura
authors.initials: L
authors.lastname: Roccograndi
authors.forename: Donald M
authors.initials: DM
authors.lastname: O'Rourke
authors.forename: Nadia
authors.initials: N
authors.lastname: Dahmane
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Gong
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005909:Glioblastoma / Q000098:blood supply* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D000077204:Temozolomide
chemical_list: C494041:ETS1 protein, human; C494042:Ets1 protein, mouse; C507096:Mmp14 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D003606:Dacarbazine; D019859:Proto-Oncogene Proteins c-met; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D000077204:Temozolomide