TY - JOUR
T1 - Gene signatures associated with mouse postnatal hindbrain neural stem cells and medulloblastoma cancer stem cells identify novel molecular mediators and predict human medulloblastoma molecular classification
AU - Corno, Daniela
AU - Pala, Mauro
AU - Cominelli, Manuela
AU - Cipelletti, Barbara
AU - Leto, Ketty
AU - Croci, Laura
AU - Barili, Valeria
AU - Brandalise, Federico
AU - Melzi, Raffaella
AU - Di Gregorio, Alessandra
AU - Sergi, Lucia Sergi
AU - Politi, Letterio Salvatore
AU - Piemonti, Lorenzo
AU - Bulfone, Alessandro
AU - Rossi, Paola
AU - Rossi, Ferdinando
AU - Consalez, Gian Giacomo
AU - Poliani, Pietro Luigi
AU - Galli, Rossella
PY - 2012/6
Y1 - 2012/6
N2 - Medulloblastoma arises from mutations occurring in stem/progenitor cells located in restricted hindbrain territories. Here we report that the mouse postnatal ventricular zone lining the IV ventricle also harbors bona fide stem cells that, remarkably, share the same molecular profile with cerebellar white matter-derived neural stem cells (NSC). To identify novel molecular mediators involved in medulloblastomagenesis, we compared these distinct postnatal hindbrain-derived NSC populations, which are potentially tumor initiating, with murine compound Ptch/p53 mutant medulloblastoma cancer stem cells (CSC) that faithfully phenocopy the different variants of human medulloblastoma in vivo. Transcriptome analysis of both hindbrain NSCs and medulloblastoma CSCs resulted in the generation of well-defined gene signatures, each reminiscent of a specific human medulloblastoma molecular subclass. Most interestingly, medulloblastoma CSCs upregulated developmentally related genes, such as Ebfs, that were shown to be highly expressed in human medulloblastomas and play a pivotal role in experimental medulloblastomagenesis. These data indicate that gene expression analysis of medulloblastoma CSCs holds great promise not only for understanding functional differences between distinct CSC populations but also for identifying meaningful signatures that might stratify medulloblastoma patients beyond histopathologic staging. SIGNIFICANCE: The functional and molecular comparison between the cell progenitor lineages from which medulloblastoma is thought to arise and medulloblastoma CSCs might lead to the identification of novel, potentially relevant mediators of medulloblastomagenesis. Our findings provide a rationale for the exploitation of mouse CSCs as a valuable preclinical model for human medulloblastoma, both for the definition of CSC-associated gene signatures with predictive mean and for the identification of therapeutically targetable genes.
AB - Medulloblastoma arises from mutations occurring in stem/progenitor cells located in restricted hindbrain territories. Here we report that the mouse postnatal ventricular zone lining the IV ventricle also harbors bona fide stem cells that, remarkably, share the same molecular profile with cerebellar white matter-derived neural stem cells (NSC). To identify novel molecular mediators involved in medulloblastomagenesis, we compared these distinct postnatal hindbrain-derived NSC populations, which are potentially tumor initiating, with murine compound Ptch/p53 mutant medulloblastoma cancer stem cells (CSC) that faithfully phenocopy the different variants of human medulloblastoma in vivo. Transcriptome analysis of both hindbrain NSCs and medulloblastoma CSCs resulted in the generation of well-defined gene signatures, each reminiscent of a specific human medulloblastoma molecular subclass. Most interestingly, medulloblastoma CSCs upregulated developmentally related genes, such as Ebfs, that were shown to be highly expressed in human medulloblastomas and play a pivotal role in experimental medulloblastomagenesis. These data indicate that gene expression analysis of medulloblastoma CSCs holds great promise not only for understanding functional differences between distinct CSC populations but also for identifying meaningful signatures that might stratify medulloblastoma patients beyond histopathologic staging. SIGNIFICANCE: The functional and molecular comparison between the cell progenitor lineages from which medulloblastoma is thought to arise and medulloblastoma CSCs might lead to the identification of novel, potentially relevant mediators of medulloblastomagenesis. Our findings provide a rationale for the exploitation of mouse CSCs as a valuable preclinical model for human medulloblastoma, both for the definition of CSC-associated gene signatures with predictive mean and for the identification of therapeutically targetable genes.
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U2 - 10.1158/2159-8290.CD-11-0199
DO - 10.1158/2159-8290.CD-11-0199
M3 - Article
C2 - 22628409
AN - SCOPUS:84866335047
VL - 2
SP - 554
EP - 568
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 6
ER -