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Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
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2012 (English)In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 21, no 5, 601-613 p.Article in journal (Refereed) Published
Abstract [en]

The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally stabilized murine N-myc(T58A) into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem, and forebrain. Transplantation of N-myc(WT) NSCs was insufficient for tumor formation. N-myc(T58A) cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating Sonic Hedgehog (SHH) dependence and SHH independence, respectively. These differences were regulated in part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal.

Place, publisher, year, edition, pages
2012. Vol. 21, no 5, 601-613 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-176237DOI: 10.1016/j.ccr.2012.04.012ISI: 000304214100005OAI: oai:DiVA.org:uu-176237DiVA: diva2:535209
Available from: 2012-06-19 Created: 2012-06-18 Last updated: 2016-03-09Bibliographically approved
In thesis
1. The Role of SOX9 in Medulloblastoma
Open this publication in new window or tab >>The Role of SOX9 in Medulloblastoma
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Overall survival is about 70% and in cases where current treatment fails, the disease recurs and most often is fatal. At the molecular level, MB can be divided into four defined subgroups: WNT, SHH, Group 3 and Group 4. Amplification of MYC family genes is common in MB and correlates with poor prognosis and tumor relapse.

In this thesis we showed how MYCN initiates brain tumors when transduced in neural stem cells (NSCs). Prior to transduction, NSCs were isolated from different brain regions and at various time points. While overexpression of wild-type MYCN did not generate any tumors, orthotopic transplantation of MYCNT58A-expressing forebrain, brain stem and cerebellar NSCs induced diffuse malignant glioma, PNET-like tumors and MB, respectively. Interestingly, MYCNT58A-expressing cerebellar NSCs induced SHH-dependent MB from embryonic cells but SHH-independent MB from postnatal cells. We further showed that cerebellar NSCs transduced with both MYCNT58A and transcription factor SOX9 developed tumors faster and promoted distant migration into the forebrain.

The function and regulation of SOX9 in MB cells is poorly understood. We identified SOX9 protein as target of FBW7 ubiquitin ligase and demonstrated the effects of SOX9 on MB cells migration, metastasis and drug resistance. We further blocked PI3K pathway to destabilize SOX9 which sensitized cells to cytostatic treatment.

We used a (TetOFF) transgenic mouse model of MYCN-induced MB (GTML) and crossed it with a (TetON) transgene which allowed us to specifically target rare SOX9-positive cells in the tumor. In this system, MB develops spontaneously and SOX9-negative tumor cells can be killed off by doxycycline. The few remaining SOX9-positive cancer cells were able to promote distant MB recurrences. Such a pattern of relapse was recently shown for Group 3 and 4 human MB where about 90% of the recurrences were distant.

In summary, this thesis demonstrates that MYCN can generate various types of brain tumors depending on the timing and location of its expression. It further defines the existence of a rare population of SOX9-expressing MB cells that are involved in causing distant MB recurrences. Finally, it describes how SOX9 is stabilized in MB cells and increases MB migration and therapy resistance.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 39 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1175
Medulloblastoma, SOX9, MYCN, cancer development, recurrence, regulation, tumor metastasis, migration
National Category
Cell and Molecular Biology Cancer and Oncology Pediatrics
Research subject
Medical Science
urn:nbn:se:uu:diva-274630 (URN)978-91-554-9461-2 (ISBN)
Public defence
2016-03-11, Rudbecksalen, Dag Hammarskjоlds vаg 20, Uppsala, 09:15 (English)
Available from: 2016-02-18 Created: 2016-01-24 Last updated: 2016-03-09

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