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| 2. |
- 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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| 4. |
- 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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| 5. |
- Brooks, Samantha J., et al.
(författare)
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Exposure to subliminal arousing stimuli induces robust activation in the amygdala, hippocampus, anterior cingulate, insular cortex and primary visual cortex : A systematic meta-analysis of fMRI studies
- 2012
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 59:3, s. 2962-2973
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Forskningsöversikt (refereegranskat)abstract
- Functional Magnetic Resonance Imaging (fMRI) demonstrates that the subliminal presentation of arousing stimuli can activate subcortical brain regions independently of consciousness-generating top-down cortical modulation loops. Delineating these processes may elucidate mechanisms for arousal, aberration in which may underlie some psychiatric conditions. Here we are the first to review and discuss four Activation Likelihood Estimation (ALE) meta-analyses of fMRI studies using subliminal paradigms. We find a maximum of 9 out of 12 studies using subliminal presentation of faces contributing to activation of the amygdala, and also a significantly high number of studies reporting activation in the bilateral anterior cingulate, bilateral insular cortex, hippocampus and primary visual cortex. Subliminal faces are the strongest modality, whereas lexical stimuli are the weakest. Meta-analyses independent of studies using Regions of Interest (ROI) revealed no biasing effect Core neuronal arousal in the brain, which may be at first independent of conscious processing, potentially involves a network incorporating primary visual areas, somatosensory, implicit memory and conflict monitoring regions. These data could provide candidate brain regions for the study of psychiatric disorders associated with aberrant automatic emotional processing.
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| 6. |
- Hede, Sanna-Maria, et al.
(författare)
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Oncoprotein stabilization in brain tumors
- 2014
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 33:39, s. 4709-4721
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Forskningsöversikt (refereegranskat)abstract
- Proteins involved in promoting cell proliferation and viability need to be timely expressed and carefully controlled for the proper development of the brain but also efficiently degraded in order to prevent cells from becoming brain cancer cells. A major pathway for targeted protein degradation in cells is the ubiquitin-proteasome system (UPS). Oncoproteins that drive tumor development and tumor maintenance are often deregulated and stabilized in malignant cells. This can occur when oncoproteins escape degradation by the UPS because of mutations in either the oncoprotein itself or in the UPS components responsible for recognition and ubiquitylation of the oncoprotein. As the pathogenic accumulation of an oncoprotein can lead to effectively sustained cell growth, viability and tumor progression, it is an indisputable target for cancer treatment. The most common types of malignant brain tumors in children and adults are medulloblastoma and glioma, respectively. Here, we review different ways of how deregulated proteolysis of oncoproteins involved in major signaling cancer pathways contributes to medulloblastoma and glioma development. We also describe means of targeting relevant oncoproteins in brain tumors with treatments affecting their stability or therapeutic strategies directed against the UPS itself.
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| 7. |
- Rahmanto, Aldwin Suryo, et al.
(författare)
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FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma
- 2016
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Ingår i: EMBO Journal. - : EMBO. - 0261-4189 .- 1460-2075. ; 35:20, s. 2192-2212
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
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| 10. |
- Savov, Vasil, 1986-
(författare)
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The Role of SOX9 in Medulloblastoma
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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