| 1. |
- Mainwaring, Oliver, et al.
(författare)
-
ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors
- 2023
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14
-
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.
|
|
| 2. |
- Bolin, Sara, 1988-, et al.
(författare)
-
Dormant SOX9-positive cells behind MYC-driven medulloblastoma recurrence
-
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.
|
|
| 3. |
- Borgenvik, Anna, et al.
(författare)
-
CDK2 as a therapeutic target in MYC-driven medulloblastoma
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Group 3 medulloblastoma (MB) is a malignant pediatric brain tumor that shows aberrant cell cycle activation, therapy resistance, and poor prognosis. Here, we identified that MYC expression and poor prognosis in Group 3 MB correlates with elevated levels of core cell cycle members CDK2 and cyclin A2, suggesting they would be promising targets for direct inhibition. Tumor cells in a novel transgenic MYC-driven MB mouse model further displayed increased p27 levels, decreased viability, and cell growth in vitro upon conditional CDK2 depletion using tamoxifen-induced recombination. Human Group 3 MB cells transduced with dominant-negative CDK2 mutants similarly exhibited decreased viability and increased p27 activation. As compared to controls, CDK2-depleted cells responded less to CDK2-specific inhibitors but were not more sensitive to BET inhibition or CDK4/6 inhibition as previously proposed. We finally used global transcriptional profiling and found that mTOR and B-Myb/ZMYM2 signaling pathways are compensating for CDK2 loss in Group 3MB cells. Our analysis suggests that specific inhibitors of these pathways could in combination with approved cell cycle inhibitors provide more efficient treatments for this severe childhood brain cancer.
|
|
| 4. |
- Čančer, Matko, et al.
(författare)
-
Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy
- 2019
-
Ingår i: Cell Stem Cell. - : CELL PRESS. - 1934-5909 .- 1875-9777. ; 25:6, s. 855-870
-
Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma (MB), the most frequent malignant childhood brain tumor, can arise from cellular malfunctions during hindbrain development. Here we generate humanized models for Sonic Hedgehog (SHH)-subgroup MB via MYCN overexpression in primary human hindbrain-derived neuroepithelial stem (hbNES) cells or iPSC-derived NES cells, which display a range of aggressive phenotypes upon xenografting. iPSC-derived NES tumors develop quickly with leptomeningeal dissemination, whereas hbNES-derived cells exhibit delayed tumor formation with less dissemination. Methylation and expression profiling show that tumors from both origins recapitulate hallmarks of infant SHH MB and reveal that mTOR activation, as a result of increased Oct4, promotes aggressiveness of human SHH tumors. Targeting mTOR decreases cell viability and prolongs survival, showing the utility of these varied models for dissecting mechanisms mediating tumor aggression and demonstrating the value of humanized models for a better understanding of pediatric cancers.
|
|
| 5. |
- Colas, Kilian, et al.
(författare)
-
Indolylbenzothiadiazoles as highly tunable fluorophores for imaging lipid droplet accumulation in astrocytes and glioblastoma cells
- 2021
-
Ingår i: RSC Advances. - : Royal Society of Chemistry. - 2046-2069. ; 11:39, s. 23960-23967
-
Tidskriftsartikel (refereegranskat)abstract
- We present an extensive photophysical study of a series of fluorescent indolylbenzothiadiazole derivatives and their ability to specifically image lipid droplets in astrocytes and glioblastoma cells. All compounds in the series displayed positive solvatochromism together with large Stokes shifts, and π-extended derivatives exhibited elevated brightness. It was shown that the fluorescence properties were highly tunable by varying the electronic character or size of the N-substituent on the indole motif. Three compounds proved capable as probes for detecting small quantities of lipid deposits in healthy and cancerous brain cells. In addition, all twelve compounds in the series were predicted to cross the blood–brain barrier, which raises the prospect for future in vivo studies for exploring the role of lipid droplets in the central nervous system.
|
|
| 6. |
- Doloczki, Susanne, et al.
(författare)
-
Photoinduced ring‐opening and phototoxicity of an indolin‐3‐one derivative
- 2023
-
Ingår i: Chemistry - A European Journal. - : John Wiley & Sons. - 0947-6539 .- 1521-3765. ; 29:51
-
Tidskriftsartikel (refereegranskat)abstract
- The study of a fluorescent indolin-3-one derivative is reported that, as opposed to its previously described congeners, selectively undergoes photoactivated ring-opening in apolar solvents. The excited state involved in this photoisomerization was partially deactivated by the formation of singlet oxygen. Cell studies revealed lipid droplet accumulation and efficient light-induced cytotoxicity.
|
|
| 7. |
- Holmberg Olausson, Karl
(författare)
-
Molecular subclassification, stem cell markers and growth regulatory pathways in gliomas
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma is the most common and aggressive primary brain tumor in adults. Median survival is no more than 15 months, even with combined treatment regimens. The lack of accurate pre-clinical model systems has limited the development of new treatment options for this deadly disease. In the first study we set out with the goal of creating improved research models for studying the disease. To this end we generated a glioblastoma patient derived cell line (PDCL) library. PDCLs grown under neural stem cell conditions functionally isolate glioblastoma cells with stem-like properties. In keeping with their cancer stem cell like nature PDCLs readily formed patient derived xenografts (PDXs) when transplanted in vivo, recapitulating histological features and maintaining genetic/protein profiles of founding tumors. Expression profiling of PDCLs revealed 4 in vitro subclasses differentially associated with WNT/B-catenin, TGF-B, BMP, Interferon, Notch and p53 signaling. Applying these new in vitro PDCL-classes to glioblastoma patient data generated clinically relevant subclasses with differences in age and survival. Hence, new PDCL models represent the original disease including aspects such as genomics/proteomics, intratumoral heterogeneity and cancer stem cell biology. In addition to functional isolation of stem-like cells using PDCL methods there have been several proteins proposed to distinguish cancer stem cells (CSCs). The most popular such protein is Prominin- 1 (PROM1/CD133). In the second study we investigated Prominin-1 expression in the developing CNS and glioblastoma. Prominin-1 is expressed in the ventricular zone of the embryonic brain and postnatally shifts to a pattern of distributed cells. The adult murine Prom1+ cell population mainly consists of Olig2+ slow cycling glial cells. Further, we established that Prom1 is independent of Olig2. Human normal brain PROM1 is associated with GFAP and SOX2. In glioblastoma PDCLs PROM1+ cells can express GFAP, SOX2 and OLIG2. PROM1 patterns are very heterogeneous across PDCLs and patient samples revealed that high PROM1 expression is less common in IDH1 mutant samples. In the third and fourth studies we investigated the possible functions of NPM1 in glioblastoma. NPM1 is a nucleolar chaperone protein highly upregulated in glioblastoma tissue samples and cell lines. We showed that NPM1 regulated the morphology of the nucleolus. This is likely due to NPM1 interacting with proteins implicated in the organization of chromatin such as HP1γ, H1.5 and H3. We also found that NPM1/DNMT3A co-depletion induced rDNA transcription and nucleolar normalization. Although DNMT3A loss upregulated rDNA transcription on its own depletion of NPM1 increased this effect suggesting NPM1 loss creates a permissive environment for further epigenetic change. NPM1 depletion sensitized glioblastoma cell lines to chemotherapy and further insults to chromatin stability such as the co-depletion of H1.5, implying NPM1 as a novel drug target. This thesis characterizes a glioblastoma PDCL library, illustrating the benefits of these new research models and addresses the complex expression of Prominin-1 and function of NPM1 with regards to molecular subclasses and growth regulatory pathways in glioblastoma, respectively.
|
|
| 8. |
- Holmberg Olausson, Karl O., et al.
(författare)
-
Drivers Underlying Metastasis and Relapse in Medulloblastoma and Targeting Strategies
- 2024
-
Ingår i: Cancers. - : MDPI. - 2072-6694. ; 16:9
-
Forskningsöversikt (refereegranskat)abstract
- Simple Summary In this review, we summarize reported molecular mechanisms underlying tumor progression and relapse of medulloblastoma, one of the most frequent malignant pediatric brain tumor entities. Medulloblastoma relapses are difficult to treat, and patients have, overall, a poor prognosis. Apart from describing the biology promoting brain tumor spread, the review will also highlight important preclinical models used to study leptomeningeal disease and recurrence. Finally, we identified clinical trials for medulloblastoma relapse and will discuss novel attempts to target therapy-escaping cancer cells responsible for recurrence.Abstract Medulloblastomas comprise a molecularly diverse set of malignant pediatric brain tumors in which patients are stratified according to different prognostic risk groups that span from very good to very poor. Metastasis at diagnosis is most often a marker of poor prognosis and the relapse incidence is higher in these children. Medulloblastoma relapse is almost always fatal and recurring cells have, apart from resistance to standard of care, acquired genetic and epigenetic changes that correlate with an increased dormancy state, cell state reprogramming and immune escape. Here, we review means to carefully study metastasis and relapse in preclinical models, in light of recently described molecular subgroups. We will exemplify how therapy resistance develops at the cellular level, in a specific niche or from therapy-induced secondary mutations. We further describe underlying molecular mechanisms on how tumors acquire the ability to promote leptomeningeal dissemination and discuss how they can establish therapy-resistant cell clones. Finally, we describe some of the ongoing clinical trials of high-risk medulloblastoma and suggest or discuss more individualized treatments that could be of benefit to specific subgroups.
|
|
| 9. |
|
|
| 10. |
- Krona, Cecilia, et al.
(författare)
-
GLIOBLASTOMA GROWTH IS SHAPED BY INVASION ROUTE-SPECIFIC FUNCTIONAL SIGNATURES
- 2023
-
Ingår i: Neuro-Oncology. - 1522-8517. ; 25:Supplement: 5, MODL-16
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- One of the defining features of glioblastomas (GBMs) is the capacity for invasive growth along multiple anatomical pathways in the brain. GBM is well-studied on a genetic and molecular level, but clinically relevant and experimentally tractable models of invasive growth are largely lacking. Here, we report an integrated study of patient-matched information, genomic- and molecular profiles with growth in mouse brains to expose treatments and biomarkers associated with glioblastoma invasion and recurrence. In total, 64 patient-derived cell lines (PDCLs) were injected into the striatum of n ≥ 4 mice each. The 45 tumor-forming PDCLs were each scored for 10 distinct growth characteristics (n = 182 mice). The repertoire of phenotypes was highly divergent, and our material included clear cases of perivascular route invasion, white matter route invasion, perineuronal satellitosis, and gliosarcoma. We explored if cellular pathways, monitored by RNA-sequencing, could account for these differences. GSEA highlighted a positive enrichment for highly proliferative proneural tumors characterized by Notch activation, neuronal signaling, and epigenetic gene regulatory programs in the tumor-initiating lines. Transcriptional signatures were also strongly predictive of route-specific invasion. Diffuse invasion was predominantly seen in classical-subtype PDCLs with astrocytic or outer radial glia-like signatures. Proneural PDCLs, in turn, grew as solid tumors with an invasive peripheral region around vasculature, and mesenchymal tumors were more demarcated. To explore the therapeutic implications of our findings, we used our data-driven method (TargetTranslator, Nat Comm 2020) to predict the drug vulnerabilities of different types of invasive glioblastoma. Defined GBM tumors with perivascular invasion are characterized by increased IGFR1, MAPK/ERK, PI3K/AKT/mTOR, and JAK2 signaling. Diffusively growing GBM tumors, on the other hand, depend more on Wnt/β-catenin signaling, neuronal signaling, and active inflammatory response. Using a sphere invasion assay, we confirm that targeting both PI3K- and Wnt signaling selectively reduces glioblastoma invasion, highlighting their therapeutic potential.
|
|
| 11. |
|
|
| 12. |
|
|
