Sox2 requirement in sonic hedgehog-associated medulloblastoma

TY - JOUR

T1 - Sox2 requirement in sonic hedgehog-associated medulloblastoma

AU - Ahlfeld, Julia

AU - Favaro, Rebecca

AU - Pagella, Pierfrancesco

AU - Kretzschmar, Hans A

AU - Nicolis, Silvia

AU - Schüller, Ulrich

N1 - ©2013 AACR.

PY - 2013/6/15

Y1 - 2013/6/15

N2 - The transcription factor Sox2 has been shown to play essential roles during embryonic development as well as in cancer. 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 show that cerebellar granule neuron precursors (CGNP), 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.

AB - The transcription factor Sox2 has been shown to play essential roles during embryonic development as well as in cancer. 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 show that cerebellar granule neuron precursors (CGNP), 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.

KW - Adolescent

KW - Adult

KW - Animals

KW - Cells, Cultured

KW - Cerebellar Neoplasms

KW - Cerebellum

KW - Child

KW - Child, Preschool

KW - Female

KW - Hedgehog Proteins

KW - Humans

KW - Immunohistochemistry

KW - Infant

KW - Male

KW - Medulloblastoma

KW - Mice

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Middle Aged

KW - Neural Stem Cells

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - SOXB1 Transcription Factors

KW - Young Adult

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1158/0008-5472.CAN-13-0238

DO - 10.1158/0008-5472.CAN-13-0238

M3 - SCORING: Journal article

C2 - 23596255

VL - 73

SP - 3796

EP - 3807

JO - CANCER RES

JF - CANCER RES

SN - 0008-5472

IS - 12

ER -