Cerebellar stem cells act as medulloblastoma-initiating cells in a mouse model and a neural stem cell signature characterizes a subset of human medulloblastomas

Sutter, Reto; Shakhova, Olga; Bhagat, Heeta; Behesti, Hourinaz; Sutter, C; Penkar, S; Santuccione, Antonella; Bernays, René L.; Heppner, Frank L.; Schüller, Ulrich; Grotzer, Michael A.; Moch, Holger; Schraml, Peter; Marino, Silvia

doi:10.1038/onc.2009.472

Cited by 72 publications

(70 citation statements)

References 49 publications

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“…The gene ontology analysis on the data obtained, allowed identifying pathways that are known already to have a role in onset and progression of MB, but which had not been correlated yet with MYC expression. In particular, we found several components of the BMP/SMAD pathway, known to be physiologically active during embryogenesis, promoting cell proliferation and differentiation of precursor cells of the cerebellum, from which MB arises (Thompson et al, 2006;Gilbertson and Ellison, 2008;Behesti and Marino, 2009;Sutter et al, 2010). Several in vivo MB models confirmed that an unbalance of proliferative/ differentiation signals, due to aberrant regulation of these pathways, can induce MB tumor formation ( Polkinghorn and Tarbell, 2007).…”

Section: Discussionmentioning

confidence: 66%

“…Effect of MYC modulation on components of the BMP pathway Growing evidence suggests the functional relevance of BMPs in the onset of a subset of MB tumors, which is currently attributed to abnormal development of GNP cells of the external granular layer of the cerebellum (Marino, 2005;Crawford et al, 2007;Gilbertson and Ellison, 2008;Sutter et al, 2010). Interestingly, several members of the BMP pathway were differentially expressed following overexpression or silencing of MYC (Table 1), suggesting a regulatory effect of MYC on this pathway in MB.…”

Section: B)mentioning

confidence: 99%

“…Finally, because of the relevance of BMPs during cerebellum development (by regulating proliferation, cell cycle exit, migration and differentiation of GNPs; Gilbertson and Ellison, 2008), it is not surprising that BMPs are likely to have a role in tumorigenesis and at least in a subset of MB tumors (Thompson et al, 2006;Grimmer and Weiss, 2008;Behesti and Marino, 2009;Sutter et al, 2010). In this respect, our experimental results are consistent with this biological hypothesis and provide an important contribution by linking, for the first time, a BMP family member to the oncogene MYC, in the context of MYC-dependent prosurvival mechanisms in MB.…”

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confidence: 99%

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Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma

et al. 2011

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Medulloblastoma (MB) is the most common malignant brain tumor in children. It is known that overexpression and/or amplification of the MYC oncogene is associated with poor clinical outcome, but the molecular mechanisms and the MYC downstream effectors in MB remain still elusive. Besides contributing to elucidate how progression of MB takes place, most importantly, the identification of novel MYC-target genes will suggest novel candidates for targeted therapy in MB. A group of 209 MYC-responsive genes was obtained from a complementary DNA microarray analysis of a MB-derived cell line, following MYC overexpression and silencing. Among the MYC-responsive genes, we identified the members of the bone morphogenetic protein (BMP) signaling pathway, which have a crucial role during the development of the cerebellum. In particular, the gene BMP7 was identified as a direct target of MYC. A positive correlation between MYC and BMP7 expression was documented by analyzing two distinct sets of primary MB samples. Functional studies in vitro using a small-molecule inhibitor of the BMP/SMAD signaling pathway reproduced the effect of the small interfering RNA-mediated silencing of BMP7. Both approaches led to a block of proliferation in a panel of MB cells and to inhibition of SMAD phosphorylation. Altogether, our findings indicate that high MYC levels drive BMP7 overexpression, promoting cell survival in MB cells. This observation suggests the potential relevance of targeting the BMP/SMAD pathway as a novel therapeutic approach for the treatment of childhood MB.

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Section: Discussionmentioning

confidence: 66%

Section: B)mentioning

confidence: 99%

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confidence: 99%

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Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma

et al. 2011

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“…Many mouse models have elegantly established that CD133 þ ventricular zone stem cells are distinct from Math1 þ external granule layer cells (Lee et al, 2005Gibson et al, 2010), and strong evidence suggests that although non-hedgehog pathway medulloblastoma may originate from the former, the Shh subtype of medulloblastoma likely originates from the latter (Rao et al, 2004;Schuller et al, 2008;Read et al, 2009;Sutter et al, 2010). Our application of BTIC culture conditions to human primary medulloblastomas and medulloblastoma cell lines allows for the enrichment of both stem and progenitor cell populations that exist within tumor spheres.…”

Section: Shh Regulates Bmi1 In Medulloblastoma Bticsmentioning

confidence: 99%

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

et al. 2011

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Bmi1 is a key stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including medulloblastoma. Overexpression of Bmi1 promotes cell proliferation and is required for hedgehog (Hh) pathwaydriven tumorigenesis. This study aimed to determine if Sonic hedgehog (Shh) modulates the key stem cell regulatory gene Bmi1 in childhood medulloblastoma brain tumor-initiating cells (BTICs). Although current literature suggests that there is a correlation between Shh pathway genes and Bmi1 expression, it is unclear whether there is indeed a direct regulatory mechanism. To address whether Shh induces expression of Bmi1, stem cell-enriched populations from medulloblastoma cell lines and primary samples were treated with Shh ligand and KAAD-cyclopamine (Shh antagonist). Our data indicate that Bmi1 expression positively correlates with increasing Shh ligand concentrations. Chromatin immunoprecipitation reveals that Gli1 preferentially binds to the Bmi1 promoter, and Bmi1 transcript levels are increased and decreased by Gli1 overexpression and downregulation, respectively. Knockdown experiments of Bmi1 in vitro and in vivo demonstrate that Hh signaling not only drives Bmi1 expression, but a feedback mechanism exists wherein downstream effectors of Bmi1 may, in turn, activate Hh pathway genes. These findings implicate Bmi1 and Hh as mutually indispensable pathways in medulloblastoma BTIC maintenance. Recent molecular characterization of medulloblastoma also reveals that Bmi1 is overexpressed across all subgroups of medulloblastoma, particularly in the most aggressive subtypes. Lastly, despite recent identification of BTIC markers, the molecular characterization of these cell populations remains unclear. In this work, we propose that the BTIC marker CD133 may segregate a cell population with a Hh-receptor phenotype, thus demonstrating a cell-cell interaction between the CD133 þ Hh receptor cells and the CD133À Hh-secreting cells.

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“…Moreover, MBs derived from mice injected with Rb-and p53-inactivated NSCs, overexpress the stem cell markers nestin, Sox2, and Sox9. These markers have also been shown to identify a subset of human MB patients with poor clinical outcome (72).…”

Section: Non-shh/wnt Subtype Mbmentioning

confidence: 99%

Medulloblastoma stem cells: where development and cancer cross pathways

et al. 2012

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Brain tumors are the leading cause of childhood cancer mortality, with medulloblastoma (MB) representing the most frequent malignant tumor. The recent molecular classification of MB has reconceptualized the heterogeneity that exists within pathological subtypes by giving context to the role of key developmental signaling pathways in MB pathogenesis. The identification of cancer stem cell (csc) populations, termed brain tumor-initiating cells (BTIcs), in MB has provided novel cellular targets for the study of these aberrantly activated signaling pathways, namely, sonic hedgehog (shh) and Wingless (Wnt), along with the identification of novel BTIc self-renewal pathways. In this review, we discuss recent evidence for the presence of a MB stem cell that drives tumorigenesis in this malignant childhood tumor. We focus on evidence from cerebellar development, the recent identification of BTIcs, the presence of activated developmental signaling pathways in MB, the role of epigenetic stem cell regulatory mechanisms, and how these developmental and epigenetic pathways may be targeted for novel therapeutic options.

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Cerebellar stem cells act as medulloblastoma-initiating cells in a mouse model and a neural stem cell signature characterizes a subset of human medulloblastomas

Cited by 72 publications

References 49 publications

Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma

Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

Medulloblastoma stem cells: where development and cancer cross pathways

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