The MET oncogene is a functional marker of a glioblastoma stem cell subtype.
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.
IRCC-Institute for Cancer Research, Center for Experimental Clinical Molecular Oncology, University of Turin Medical School, Candiolo, Italy.
Francesca
F
De Bacco
Elena
E
Casanova
Enzo
E
Medico
Serena
S
Pellegatta
Francesca
F
Orzan
Raffaella
R
Albano
Paolo
P
Luraghi
Gigliola
G
Reato
Antonio
A
D'Ambrosio
Paola
P
Porrati
Monica
M
Patanè
Emanuela
E
Maderna
Bianca
B
Pollo
Paolo M
PM
Comoglio
Gaetano
G
Finocchiaro
Carla
C
Boccaccio
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D055815:Young Adult
D014408:Biomarkers, Tumor; D008024:Ligands; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met