An ILK/STAT3 pathway controls glioblastoma stem cell plasticity
Alexander E.P. Loftus, Marianna S. Romano, Anh Nguyen Phuong, Ben J McKinnel, Morwenna Muir, Muhammad Furqan, John C. Dawson, Lidia Avalle, Adam Douglas, Richard L. Mort, Adam Byron, Neil O. Carragher, Steven M. Pollard, Valerie G. Brunton, Margaret C. Frame
Abstract
Glioblastoma (GBM) is driven by malignant neural stem-like cells that display extensive heterogeneity and phenotypic plasticity, which drive tumor progression and therapeutic resistance. Here, we show that the extracellular matrix-cell adhesion protein integrin-linked kinase (ILK) stimulates phenotypic plasticity and mesenchymal-like, invasive behavior in a murine GBM stem cell model. ILK is required for the interconversion of GBM stem cells between malignancy-associated glial-like states, and its loss produces cells that are unresponsive to multiple cell state transition cues. We further show that an ILK/STAT3 signaling pathway controls the plasticity that enables transition of GBM stem cells to an astrocyte-like state in vitro and in vivo. Finally, we find that ILK expression correlates with expression of STAT3-regulated proteins and protein signatures describing astrocyte-like and mesenchymal states in patient tumors. This work identifies ILK as a pivotal regulator of multiple malignancy-associated GBM phenotypes, including phenotypic plasticity and mesenchymal state.