The transcription factor Sox2 has been demonstrated to play essential roles during embryonic development as well as in cancer. In order to more precisely understand tumor biology and to identify potential therapeutical targets we thoroughly investigated the expression and function of Sox2 in medulloblastoma, a malignant embryonic brain tumor that initiates in the posterior fossa and eventually spreads throughout the entire cerebrospinal axis. We examined a large series of tumor samples (n=188) to show that SOX2 is specifically expressed in Sonic hedgehog (SHH)-associated medulloblastoma with an interesting preponderance in adolescent and adult cases. We further demonstrate that cerebellar granule neuron precursors (CGNPs), which are believed to serve as the cell of origin for this medulloblastoma subgroup, express Sox2 in early stages. Also, Shh-associated medulloblastoma can be initiated from such Sox2-positive CGNPs in mice. Independent of their endogenous Sox2 expression, constitutive activation of Shh-signaling in CGNPs resulted in significantly enhanced proliferation and ectopic expression of Sox2 in vitro and Sox2-positive medulloblastoma in vivo. Genetic ablation of Sox2 from murine medulloblastoma did not affect survival, most likely due to a compensatory overexpression of Sox3. However, acute deletion of Sox2 from primary cultures of CGNPs with constitutive Shh-signaling significantly decreased proliferation whereas overexpression of Sox2 enhanced proliferation of murine medulloblastoma cells. We conclude that Sox2 is a marker for Shh-dependent medulloblastomas where it is required and sufficient to drive tumor cell proliferation.

Ahlfeld, J., Favaro, R., Pagella, P., Kretzschmar, H., Nicolis, S., Schüller, U. (2013). Sox2 requirement in Sonic hedgehog-associated medulloblastoma. CANCER RESEARCH, 73(12), 3796-3807 [10.1158/0008-5472.CAN-13-0238].

Sox2 requirement in Sonic hedgehog-associated medulloblastoma

FAVARO, REBECCA;NICOLIS, SILVIA KIRSTEN;
2013

Abstract

The transcription factor Sox2 has been demonstrated to play essential roles during embryonic development as well as in cancer. In order to more precisely understand tumor biology and to identify potential therapeutical targets we thoroughly investigated the expression and function of Sox2 in medulloblastoma, a malignant embryonic brain tumor that initiates in the posterior fossa and eventually spreads throughout the entire cerebrospinal axis. We examined a large series of tumor samples (n=188) to show that SOX2 is specifically expressed in Sonic hedgehog (SHH)-associated medulloblastoma with an interesting preponderance in adolescent and adult cases. We further demonstrate that cerebellar granule neuron precursors (CGNPs), which are believed to serve as the cell of origin for this medulloblastoma subgroup, express Sox2 in early stages. Also, Shh-associated medulloblastoma can be initiated from such Sox2-positive CGNPs in mice. Independent of their endogenous Sox2 expression, constitutive activation of Shh-signaling in CGNPs resulted in significantly enhanced proliferation and ectopic expression of Sox2 in vitro and Sox2-positive medulloblastoma in vivo. Genetic ablation of Sox2 from murine medulloblastoma did not affect survival, most likely due to a compensatory overexpression of Sox3. However, acute deletion of Sox2 from primary cultures of CGNPs with constitutive Shh-signaling significantly decreased proliferation whereas overexpression of Sox2 enhanced proliferation of murine medulloblastoma cells. We conclude that Sox2 is a marker for Shh-dependent medulloblastomas where it is required and sufficient to drive tumor cell proliferation.
Articolo in rivista - Articolo scientifico
Sox2, cancer stem cells, medulloblastoma
English
2013
73
12
3796
3807
none
Ahlfeld, J., Favaro, R., Pagella, P., Kretzschmar, H., Nicolis, S., Schüller, U. (2013). Sox2 requirement in Sonic hedgehog-associated medulloblastoma. CANCER RESEARCH, 73(12), 3796-3807 [10.1158/0008-5472.CAN-13-0238].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/43634
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