Integrin α3β1 promotes vessel formation of glioblastoma-associated endothelial cells through calcium-mediated macropinocytosis and lysosomal exocytosis

Eunnyung Bae, Ping Huang, Gaёlle Müller-Greven, Dolores Hambardzumyan, Andrew Edward Sloan, Amy S. Nowacki, Nicholas Marko, Cathleen R. Carlin and Candece L. Gladson ()
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Eunnyung Bae: Cleveland, Clinic
Ping Huang: Cleveland, Clinic
Gaёlle Müller-Greven: Cleveland, Clinic
Dolores Hambardzumyan: Icahn School of Medicine, Mount Sinai
Andrew Edward Sloan: Seidman Cancer Center
Amy S. Nowacki: Cleveland Clinic
Nicholas Marko: LewisGale Medical Center
Cathleen R. Carlin: University Hospital-Cleveland Medical Center and the Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine
Candece L. Gladson: Cleveland, Clinic

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Therapeutic targeting of angiogenesis in glioblastoma has yielded mixed outcomes. Investigation of tumor-associated angiogenesis has focused on the factors that stimulate the sprouting, migration, and hyperproliferation of the endothelial cells. However, little is known regarding the processes underlying the formation of the tumor-associated vessels. To address this issue, we investigated vessel formation in CD31+ cells isolated from human glioblastoma tumors. The results indicate that overexpression of integrin α3β1 plays a central role in the promotion of tube formation in the tumor-associated endothelial cells in glioblastoma. Blocking α3β1 function reduced sprout and tube formation in the tumor-associated endothelial cells and vessel density in organotypic cultures of glioblastoma. The data further suggest a mechanistic model in which integrin α3β1-promoted calcium influx stimulates macropinocytosis and directed maturation of the macropinosomes in a manner that promotes lysosomal exocytosis during nascent lumen formation. Altogether, our data indicate that integrin α3β1 may be a therapeutic target on the glioblastoma vasculature.

Date: 2022
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DOI: 10.1038/s41467-022-31981-2

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