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Mechanisms of Medulloblastoma Dissemination and Novel Targeted Therapies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. (Swartling)ORCID iD: 0000-0003-2835-1518
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Medulloblastomas are the most frequent malignant childhood brain tumors, arising in the posterior fossa of children. The overall 5-year survival is 70%, although children often suffer severe long-term side effects from standard medical care. To improve progression-free survival and quality of life for these children, finding new therapeutic targets in medulloblastoma is imperative.

Medulloblastoma is divided in to four molecular subgroups (WNT, SHH, Group 3 and Group 4) based on key developmental pathways essential for the initiation and maintenance of tumor development. The MYC family of proto-oncogenes regulates cell proliferation and differentiation in normal brain. Aberrant expression of MYC proteins occurs commonly in medulloblastoma.

Our studies on Group 3 medulloblastoma identify the transcription factor SOX9 as a novel target for the E3 ubiquitin ligase FBW7, and show that increased stability of SOX9 confers an increased metastatic potential in medulloblastoma. Moreover, SOX9-positive cells drive distant recurrences in medulloblastoma when combining two regulatable TetON/OFF systems. MYCN depletion leads to increased SOX9 expression in Group 3 medulloblastoma cells, and the recurring tumor cells are more migratory in vitro and in vivo. Segueing to treatment of medulloblastoma, we show that BET bromodomain inhibition specifically targets MYC-amplified medulloblastoma cells by downregulating MYC and MYC-transcriptional targets, and that combining BET bromodomain- and cyclin-dependent kinase- inhibition improves survival in mice compared to single therapy. Combination treatment results in decreased MYC levels and increased apoptosis, and RNA-seq confirms upregulation of apoptotic markers along with downregulated MYC target genes in medulloblastoma cells.

This thesis addresses novel findings in transcription factor biology, recurrence and treatment in Group 3 medulloblastoma, the most malignant subgroup of the disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1254
Keyword [en]
Medulloblastoma, Recurrence, MYC, SOX9, FBW7, Treatment, BET bromodomains, Cyclin-dependent kinases
National Category
Basic Medicine
Research subject
Oncology
Identifiers
URN: urn:nbn:se:uu:diva-300907ISBN: 978-91-554-9692-0 (print)OAI: oai:DiVA.org:uu-300907DiVA: diva2:971666
Public defence
2016-11-04, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-10-12 Created: 2016-08-15 Last updated: 2016-10-19
List of papers
1. FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma
Open this publication in new window or tab >>FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma
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2016 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 35, no 20, 2192-2212 p.Article in journal (Refereed) Published
Abstract [en]

SOX9 is a master transcription factor that regulates development and stem cell programs. However, its potential oncogenic activity and regulatory mechanisms that control SOX9 protein stability are poorly understood. Here, we show that SOX9 is a substrate of FBW7, a tumor suppressor, and a SCF (SKP1/CUL1/F-box)-type ubiquitin ligase. FBW7 recognizes a conserved degron surrounding threonine 236 (T236) in SOX9 that is phosphorylated by GSK3 kinase and consequently degraded by SCFFBW7 alpha. Failure to degrade SOX9 promotes migration, metastasis, and treatment resistance in medulloblastoma, one of the most common childhood brain tumors. FBW7 is either mutated or downregulated in medulloblastoma, and in cases where FBW7 mRNA levels are low, SOX9 protein is significantly elevated and this phenotype is associated with metastasis at diagnosis and poor patient outcome. Transcriptional profiling of medulloblastoma cells expressing a degradation-resistant SOX9 mutant reveals activation of pro-metastatic genes and genes linked to cisplatin resistance. Finally, we show that pharmacological inhibition of PI3K/AKT/mTOR pathway activity destabilizes SOX9 in a GSK3/FBW7-dependent manner, rendering medulloblastoma cells sensitive to cytostatic treatment.

Keyword
FBW7, SOX9, Medulloblastoma, FBXW7, ubiquitin, migration, metastasis, drug resistance
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-274626 (URN)10.15252/embj.201693889 (DOI)000385708000004 ()
Funder
Swedish Childhood Cancer FoundationSwedish Cancer SocietySwedish Research CouncilEU, European Research Council, 640275Ragnar Söderbergs stiftelseSwedish Society of MedicineÅke Wiberg FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceThe Karolinska Institutet's Research Foundation
Note

Aldwin Suryo Rahmanto and Vasil Savov contributed equally to this work as first authors

Andrä Brunner, Sara Bolin and Holger Weishaupt contributed equally to this work as second authors

Fredrik J Swartling and Olle Sangfelt contributed equally to this work as corresponding authors

Available from: 2016-01-24 Created: 2016-01-24 Last updated: 2017-11-30Bibliographically approved
2. Metastasis and tumor recurrence from rare SOX9-positive cells in MYCN-driven medulloblastoma
Open this publication in new window or tab >>Metastasis and tumor recurrence from rare SOX9-positive cells in MYCN-driven medulloblastoma
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(English)Manuscript (preprint) (Other academic)
Keyword
SOX9, medulloblastoma, relapse, recurrence, MYCN, mouse model, pediatric cancer
National Category
Cell and Molecular Biology Cancer and Oncology Pediatrics
Identifiers
urn:nbn:se:uu:diva-274629 (URN)
Available from: 2016-01-24 Created: 2016-01-24 Last updated: 2016-09-18
3. BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma
Open this publication in new window or tab >>BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma
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2014 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, no 4, 912-925 p.Article in journal (Refereed) Published
Abstract [en]

Purpose:

MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.

Experimental Design:

We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.

Results:

Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index.

Conclusion:

JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.

Keyword
medulloblastoma, MYC
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-217950 (URN)10.1158/1078-0432.CCR-13-2281 (DOI)000331875500015 ()
Available from: 2014-02-06 Created: 2014-02-06 Last updated: 2017-12-06Bibliographically approved
4. Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
Open this publication in new window or tab >>Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
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(English)Article in journal (Other academic) Submitted
Keyword
MYC, BET Bromodomains, Cyclin dependent kinases, Treatment, Medulloblastoma
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-300906 (URN)
Available from: 2016-08-15 Created: 2016-08-15 Last updated: 2016-10-11

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