The <i>MET</i> Oncogene Is a Functional Marker of a Glioblastoma Stem Cell Subtype

TLDR

Glioblastoma aggressiveness is driven by treatment‑resistant cancer stem cells, yet the molecular changes that promote their proliferation remain unknown. We identified MET expression as a functional marker of glioblastoma stem cells, with Met‑positive neurospheres enriched for mesenchymal/proneural signatures, exhibiting distinct growth factor dependencies, clonogenic self‑renewal, and enhanced tumorigenicity, and whose proliferation is further driven by HGF, indicating MET as a potential therapeutic target.

Abstract

The existence of treatment-resistant cancer stem cells contributes to the aggressive phenotype of glioblastoma. However, the molecular alterations that drive stem cell proliferation in these tumors remain unknown. In this study, we found that expression of the MET oncogene was associated with neurospheres expressing the gene signature of mesenchymal and proneural subtypes of glioblastoma. Met expression was almost absent from neurospheres expressing the signature of the classical subtype and was mutually exclusive with amplification and expression of the EGF receptor (EGFR) gene. Met-positive and Met-negative neurospheres displayed distinct growth factor requirements, differentiated along divergent pathways, and generated tumors with distinctive features. The Met(high) subpopulation within Met-pos neurospheres displayed clonogenic potential and long-term self-renewal ability in vitro and enhanced growth kinetics in vivo. In Met(high) cells, the Met ligand HGF further sustained proliferation, clonogenicity, expression of self-renewal markers, migration, and invasion in vitro. Together, our findings suggest that Met is a functional marker of glioblastoma stem cells and a candidate target for identification and therapy of a subset of glioblastomas.