Fibrillar extracellular matrix produced by pericyte-like cells facilitates glioma cell dissemination

Abstract

Abstract Purpose Gliomagenesis is associated with changes in extracellular matrix (ECM) composition. We investigate the role of fibroblast activation protein-positive (FAP+) pericyte-like cells in ECM alterations in glioblastoma and their impact on glioma cells. Methods Bioinformatic analysis, immunohistochemistry, and ELISA were used to evaluate the expression of ECM proteins and FAP. FAP + pericyte-like cells were isolated from human glioblastomas, ECM production was quantified by ELISA and using mass spectrometry analysis of 3D matrices. Haptotaxis and focal adhesion kinase (FAK) signaling activation assays were performed to assess the influence of the ECM on glioma cells. Results Higher FAP expression was associated with elevated levels of collagen I and fibronectin in glioblastoma. FAP + pericyte-like cells were present in regions rich in collagen I and fibronectin in biopsy material and produced substantially more collagen I and fibronectin in vitro compared to other cell types found in glioblastoma. Mass spectrometry revealed that in contrast to glioma cells, 3D matrices produced by FAP + pericyte-like cells were rich in collagen I and fibronectin and contained several key basement membrane proteins. ECM produced by FAP + pericyte-like cells enhanced migration and adhesion of glioma cells, including glioma stem-like cells, and promoted focal adhesion kinase (FAK) signaling. Conclusion This study establishes FAP + pericyte-like cells as crucial producers of an ECM rich in collagen I and fibronectin in glioblastoma microenvironment. Such ECM triggers FAK activation and facilitates the dissemination of glioma cells. Our data provide new insights into the mechanisms underlying gliomagenesis.