The interplay of Epsins and Notch in Glioblastoma
Marina Cardano, Centre for Integrative Biology CIBIO, Università degli Studi di Trento,
Via Sommarive 9, Trento, ITALY; Jacopo Zasso, Centre for Integrative Biology CIBIO, Università degli Studi di Trento, Via Sommarive 9, Trento, ITALY; Luciano Conti, Centre for Integrative Biology CIBIO, Università degli Studi di Trento, Via Sommarive 9, Trento, ITALY.
Epsin1 (EPN1) and epsin2 (EPN2) belong to a small family of evolutionarily conserved endocytic adaptors able to mediate the internalization of ubiquitinated proteins. Many reports demonstrated an essential role of this family in Notch pathway, which dysregulation is strictly connected to developmental aberrations, carcinogenesis and angiogenesis. Since Notch activation is a common signature in primary human Glioblastoma Multiforme (GBM) and GBM endothelial cells express high levels of ligands, promoting the maintenance Glioblastoma Stem Cells (GSCs) undifferentiated state, growth and renewal, we decided to evaluate EPNs contribution in such disease.
We initially demonstrated that EPNs exhibit a pivotal role in preserving Embryonic Stem Cells (ESCs) pluripotency and that their knock-down completely mis-regulate the self-renewing/differentiation programs of both Neural Stem Cells (NSCs) and GSCs, determining an increase of neuronal differentiation and affecting cell viability. Moreover, GSC lines derived from different patients are characterized by a strong up-regulation of EPNs if compared to physiological NSCs. We have also shown that EPNs control the integrity of cell junctions, corroborating the hypothesis of their involvement in a Notch-mediated EMT process.
Our data strongly suggest that EPNs can be used to unravel some of the principal GBM properties, such as stemness and invasiveness, thus representing a putative therapeutic target for this pathology.