In:
Neuro-Oncology, Oxford University Press (OUP), Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi193-vi193
Abstract:
The majority of Group 3 medulloblastomas (MB) exhibit amplification or increased expression of OTX2. OTX2 is primarily known as an oncogenic driver of tumor growth and cell cycle progression in Group 3 MB; however, its role as a repressor of differentiation is poorly characterized. Therefore, we utilized extensive patient data and mapped Group 3 MB chromatin dynamics in stem cell-enriched cultures to evaluate the divergent role of OTX2 in cell fate decisions in Group 3 MB pathogenesis. Several PAX genes were identified as novel OTX2 targets in Group 3 MB. Examination of patient data revealed that PAX3 and PAX6 expression is significantly reduced in Group 3 MB patients and is associated with significantly reduced survival. Functional evaluation of PAX3 and PAX6 expression showed that PAX3 expression significantly reduced self-renewal capacity of Group 3 MB tumorspheres in vitro and significantly prolonged survival and reduced tumor size in orthotopic xenograft models in vivo. RNA-sequencing of PAX3 and PAX6 gain of function (GOF) tumorspheres revealed mTORC1 signalling was specifically downregulated in PAX3 GOF, indicating this pathway may be critical for the survival and self-renewal differences observed between PAX3/PAX6 GOF models. Treatment of Group 3 MB with mTOR inhibitors reduced self-renewal in vitro and significantly prolonged survival and reduced tumor size in vivo. To further evaluate the role for this signalling axis in the Group 3 MB neural lineage hierarchy, we carried out scRNA-sequencing in tumorspheres from 4 Group 3 MB cell lines. Interestingly, a broad range of OTX2 expression was observed across single cell clusters, suggesting distinct OTX2 regulatory hierarchies are present in Group 3 MB. Collectively, our work demonstrates the multifaceted role of OTX2 as a regulator of cell fate decisions in Group 3 MB and identifies a novel role for mTORC1 signalling in Group 3 MB self-renewal and differentiation.
Type of Medium:
Online Resource
ISSN:
1522-8517
,
1523-5866
DOI:
10.1093/neuonc/noz175.804
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2019
detail.hit.zdb_id:
2094060-9
