| 1. |
- 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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| 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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| 3. |
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| 4. |
- Borssen, A. D., et al.
(författare)
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Histological improvement of liver fibrosis in well-treated patients with autoimmune hepatitis A cohort study
- 2017
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Ingår i: Medicine (United States). - : Ovid Technologies (Wolters Kluwer Health). - 0025-7974. ; 96:34
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune hepatitis (AIH) is a chronic autoimmune liver disease that if left untreated may lead to the development of cirrhosis. Previous studies on AIH patients have suggested that fibrosis and even cirrhosis can be reversed by medical treatment. The aim of this study was to evaluate the efficacy of medical treatment for protection of developing fibrosis and cirrhosis. A total of 258 liver biopsies from 101 patients (72 women, 29 men) were analyzed by a single pathologist and classified according to the Ishak grading (inflammation) and staging (fibrosis) system. Liver histology was stratified according to the temporal changes of fibrosis stage (increased, decreased, or stable), and groups were compared. Complete or partial response to medical treatment was 94.9%. Reduction of fibrosis stage from the first to the last biopsy was seen in 63 patients (62.4%). We found an association between a reduction in the fibrosis stage and continuous glucocorticoid medication, as well as lowered scores of inflammation at last biopsy. Twenty-one patients had cirrhosis (Ishak stage 6) at least in one of the previous biopsies, but only 5 patients at the last biopsy. Histological improvement is common in AIH patients that respond to medical treatment, and a reduction or stabilization of fibrosis stage occurs in about 2/3 of such patients.
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| 5. |
- 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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| 6. |
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| 7. |
- van Es, Michael A, et al.
(författare)
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Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis
- 2011
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Ingår i: Annals of Neurology. - : Wiley-Blackwell. - 0364-5134 .- 1531-8249. ; 70:6, s. 964-973
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD.METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios.RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD.INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.
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