Junctional adhesion molecule C limits glioblastoma stem-like cell invasion by regulating integrin adhesion at the...

While locating in different microenvironments, glioblastoma stem-like cells (GSCs) receive maintenance signals and information to exploit neurovascular tracts. Although the cell adhesion mechanisms to blood vessels have been explored, the mediators guiding GSC interaction with the endothelial cells and their matrix remain incompletely resolved. Here, we identify junctional adhesion molecule C (JAMC) as a key regulator of heterophilic and homophilic interactions of GSC to endothelial surfaces. Using decellularized matrices, co-cultures, and organotypic brain slices, we demonstrate that JAMC restrains GSC spreading. JAMC^-/- GSCs exhibit extended spreading on endothelial-borne supports, with exacerbated invasive, migratory, and mesenchymal-like behaviors, further eroding mice survival. Spatial transcriptomics of human samples confirmed the association between invasion and JAMC expression pattern. Quantitative proteomics unveiled that JAMC deletion elicits integrin upregulation, concurrent with a downregulation of the integrin negative regulator, SHARPIN. The landscape of adhesion molecules anchoring GSCs to vascular surfaces may coordinate cell migration in glioblastoma territories.