TY  - JOUR
A1  - Stromecki, Margaret
A1  - Tatari, Nazanin
A1  - Coudière Morrison, Ludivine
A1  - Kaur, Ravinder
A1  - Zagozewski, Jamie
A1  - Palidwor, Gareth
A1  - Ramaswamy, Vijay
A1  - Skowron, Patryk
A1  - Wölfl, Matthias
A1  - Milde, Till
A1  - Del Bigio, Marc R.
A1  - Taylor, Michael D.
A1  - Werbowetski-Ogilvie, Tamra E.
T1  - Characterization of a novel OTX2-driven stem cell program in Group 3 and Group 4 medulloblastoma
JF  - Molecular Oncology
N2  - Medulloblastoma (MB) is the most common malignant primary pediatric brain cancer. Among the most aggressive subtypes, Group 3 and Group 4 originate from stem/progenitor cells, frequently metastasize, and often display the worst prognosis, yet we know the least about the molecular mechanisms driving their progression. Here, we show that the transcription factor orthodenticle homeobox 2 (OTX2) promotes self-renewal while inhibiting differentiation in vitro and increases tumor initiation from MB stem/progenitor cells in vivo. To determine how OTX2 contributes to these processes, we employed complementary bioinformatic approaches to characterize the OTX2 regulatory network and identified novel relationships between OTX2 and genes associated with neuronal differentiation and axon guidance signaling in Group 3 and Group 4 MB stem/progenitor cells. In particular, OTX2 levels were negatively correlated with semaphorin (SEMA) signaling, as expression of 9 SEMA pathway genes is upregulated following OTX2 knockdown with some being potential direct OTX2 targets. Importantly, this negative correlation was also observed in patient samples, with lower expression of SEMA4D associated with poor outcome specifically in Group 4 tumors. Functional proof-of-principle studies demonstrated that increased levels of select SEMA pathway genes are associated with decreased self-renewal and growth in vitro and in vivo and that RHO signaling, known to mediate the effects of SEMA genes, is contributing to the OTX2 KD phenotype. Our study provides mechanistic insight into the networks controlled by OTX2 in MB stem/progenitor cells and reveals novel roles for axon guidance genes and their downstream effectors as putative tumor suppressors in MB.
KW  - axon guidance genes
KW  - medulloblastoma
KW  - orthodenticle homeobox 2
KW  - RHO
KW  - semaphorin
KW  - stem cells
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240089
VL  - 12
ER  -