| 1. |
- Bolin, Sara, 1988-, et al.
(författare)
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Dormant SOX9-positive cells behind MYC-driven medulloblastoma recurrence
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Tidskriftsartikel (refereegranskat)abstract
- Tumor recurrence is a slow biological process involving therapy resistance, immune escape, and metastasis and is the leading cause of death in medulloblastoma, the most frequent malignant pediatric brain tumor. By studying paired primary-recurrent patient samples and patient-derived xenografts we identified a significant accumulation of SOX9-positive cells in relapses and metastases. They exist as rare, quiescent cells in Group 3 and Group 4 patients that constitute two-thirds of medulloblastoma. To follow relapse at the single-cell level we developed an inducible dual Tet model of MYC-driven MB, where MYC can be directed from treatment-sensitive bulk cells to resistant, dormant SOX9-positive cells by doxycycline. SOX9 promoted immune es-cape, DNA repair suppression and was essential for recurrence. Tumor cell dormancy was non-hierarchical, migratory, and depended on MYC suppression by SOX9 to promote relapse. By using computational modeling and treatment we further showed how doxorubicin and MGMT inhibitors are specifically targeting relapsing cells.
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| 2. |
- Borgenvik, Anna, 1987-, et al.
(författare)
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Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
- 2022
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 82:24, s. 4586-4603
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Tidskriftsartikel (refereegranskat)abstract
- Relapse is the leading cause of death in patients with medulloblas-toma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse.Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.
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| 3. |
- Mainwaring, Oliver, et al.
(författare)
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ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma, the most common malignant pediatric brain tumor, often harbors MYC amplifications. Compared to high-grade gliomas, MYC-amplified medulloblastomas often show increased photoreceptor activity and arise in the presence of a functional ARF/p53 suppressor pathway. Here, we generate an immunocompetent transgenic mouse model with regulatable MYC that develop clonal tumors that molecularly resemble photoreceptor-positive Group 3 medulloblastoma. Compared to MYCN-expressing brain tumors driven from the same promoter, pronounced ARF silencing is present in our MYC-expressing model and in human medulloblastoma. While partial Arf suppression causes increased malignancy in MYCN-expressing tumors, complete Arf depletion promotes photoreceptor-negative high-grade glioma formation. Computational models and clinical data further identify drugs targeting MYC-driven tumors with a suppressed but functional ARF pathway. We show that the HSP90 inhibitor, Onalespib, significantly targets MYC-driven but not MYCN-driven tumors in an ARF-dependent manner. The treatment increases cell death in synergy with cisplatin and demonstrates potential for targeting MYC-driven medulloblastoma.
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| 4. |
- Mainwaring, Oliver, 1992-
(författare)
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Of Mice and MYC : Modelling Medulloblastoma
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Brain tumours are the leading cause of cancer-related paediatric deaths, with medulloblastoma (MB) being the most common malignant paediatric brain tumour. MB is stratified into four major subgroups – WNT, SHH, Group 3, and Group 4, nomenclature defined by key pathways and drivers involved within each subgroup. Group 3 MB is the most moribund subgroup of MB with a 5-year overall survival of less than 50%. It is commonly termed the ‘MYC’ subgroup due to focal high-level amplification of the MYC gene in 20% of these patients.To investigate the involvement of MYC in MB development, in paper I we generated a transgenic murine model of MYC-driven MB (GMYC) where aberrant MYC expression is constitutively driven from the Glutamate-transporter-1 (Glt1) promoter. Tumours develop spontaneously 3-6 months postnatally and recapitulate tumour histology seen in patients. Suppression of MYC in tumour-bearing mice led to clearance of cancerous cells, indicating a necessity for MYC in maintenance of GMYC tumours. Our novel GMYC model was compared to our previous GTML model (a transgenic model of Group 3 MB driven by MYCN), as well as to clinical patient data. GSEA revealed significant differences in the genetic pathways driving both mouse models. The Cdkn2a tumour suppressor gene was expressed at significantly higher levels in our GTML model compared to our GMYC model. Subsequent investigation of this gene revealed a methylation signature seen only on Group 3 patients with high MYC expression. Treatment using the HSP90 inhibitor, Onalespib, restored ARF in vitro and promoted increased survival in our animal model, suggesting its therapeutic potential for children affected with MYC-driven, ARF-silenced brain cancer.In paper II, we next investigated the putative cell-of-origin for GMYC tumours by crossing the GMYC mouse model with a fluorescent reporter system to track tumour development and comparison to normal, developing brains. In this paper, we show GMYC tumours arise from a stem/progenitor cell that likely develops in an extra-cerebellar location prior to clonal expansion and the full extent of tumour formation.Lastly, in paper III, we established transcriptional networks specific for Group 3 and 4 MB with a focus on gene interactions involving chromosome 17q genes. KIF18B was identified as one such gene located on Chr17q that may have a role in Group 4 MB pathogenesis. These transcriptional networks demonstrate a promising means of identifying novel cancer-related genes and their link to other regulatory genes known to be involved in tumourigenesis.
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| 5. |
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| 6. |
- Weishaupt, Holger, et al.
(författare)
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Prioritization of candidate cancer genes on chromosome 17q through reverse engineered transcriptional regulatory networks in medulloblastoma groups 3 and 4
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Group 3 and 4 MB present an intermediate to bad prognosis and high rates of metastasis. Amplification of (chromosome 17q) chr 17q is the most frequently observed genomic alteration in these patients and is coupled to a worsened prognosis. However, little is known about how or which genes on chr 17a contribute to the development of MB. Identification of such genes will greatly benefit from more integrative methods. Yet, functional association networks integrating multiple data types, a gold standard for such investigations, are largely missing for MB. In this project, we establish transcriptional regulatory networks of MB groups 3 and 4. Employing these networks, we were able to study the genomic events associated with MB groups 3 and 4 at a system wide level. Specifically, a focus lied on the identification of candidate cancer genes/modules on chr 17q through a network propagation strategy. Through these analyses, we have identified KIF18B as a putative, novel cancer gene of Group 4 MB, suggesting a promising potential for yet more integrative network-based studies.
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| 7. |
- Zhao, Miao, et al.
(författare)
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Photoreceptor-positive cells of tumor origin in MYC-driven Group 3 medulloblastoma
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Medulloblastoma (MB) comprises four distinct subgroups respective of genomic and molecular drivers influencing tumorigenesis. It has been established that despite being considered a single disease entity, each subgroup arises from a distinct population of cells found within unique compartments of the developing brain. The location and cell-of-origin of Group 3 MB, the most moribund of MB subgroups, is currently unknown and remains controversial. We previously developed a mouse model of MB (GMYC) where mice spontaneously develop Group 3-like tumors after 4-6 months of age, driven by over-expression of the MYC oncogene in Glutamate transporter 1 promoter (Glt1)-positive cells. We investigated and compared brain and tumor development between these mice and their control counterparts using single cell sequencing and lineage tracing. We conclude that MYC overexpression led to transformation of an immature cell population driven by photoreceptor pathway activation.
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