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.
Highlights
Glioblastoma, the highest grade glioma variant, is a relatively rare but very aggressive tumor, associated with high morbidity, mortality, and recurrence
5 of 13 neurospheres derived from EGFRamp/vIII tumors lacked EGF receptor (EGFR) alterations (Table 2)
The comparative analysis reported in this article showed that, as a rule, the same mutations of primary glioblastomas are found in their matched neurospheres
Summary
Glioblastoma, the highest grade glioma variant, is a relatively rare (yearly incidence of 4–5/100,000 people) but very aggressive tumor, associated with high morbidity, mortality, and recurrence (median survival of 12–15 months; ref. 1). Isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2), or aberrant activation of PDGFRA, resulting from gene amplification/ mutation, or occurrence of autocrine loops This subtype, often evolving from lower grade gliomas, may associate with a more favorable prognosis, but does not benefit from current therapies [6, 7]. We isolated and propagated extensively self-renewing neurospheres, that is, cultures enriched in stem and progenitor cells [12]. These neurospheres displayed mutational profiles largely overlapping with those of the original tumors and could be classified as classical, mesenchymal, or proneural, according to their gene expression profile. We associated expression of the MET oncogene with mesenchymal and proneural neurospheres, and we showed that Met signaling actively supported the stem-like and invasive phenotype
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