SwePub - search: WFRF:(Swartling Fredrik J.)

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1.	Lundgren, Markus, et al. (author) Analgesic antipyretic use among young children in the TEDDY study : No association with islet autoimmunity 2017 In: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 17:1 Journal article (peer-reviewed)abstract Background: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. Methods: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. Results: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). Conclusions: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection.
2.	Adolphe, Christelle, et al. (author) SOX9 Defines Distinct Populations of Cells in SHH Medulloblastoma but Is Not Required for Math1-Driven Tumor Formation 2021 In: Molecular Cancer Research. - : American Association For Cancer Research (AACR). - 1541-7786 .- 1557-3125. ; 19:11, s. 1831-1839 Journal article (peer-reviewed)abstract Medulloblastoma is the most common malignant pediatric brain tumor and there is an urgent need for molecularly targeted and subgroup-specific therapies. The stem cell factor SOX9, has been proposed as a potential therapeutic target for the treatment of Sonic Hedgehog medulloblastoma (SHH-MB) subgroup tumors, given its role as a downstream target of Hedgehog signaling and in functionally promoting SHH-MB metastasis and treatment resistance. However, the functional requirement for SOX9 in the genesis of medulloblastoma remains to be determined. Here we report a previously undocumented level of SOX9 expression exclusively in proliferating granule cell precursors ( GCP) of the postnatal mouse cerebellum, which function as the medulloblastoma-initiating cells of SHH-MBs. Wild-type GCPs express comparatively lower levels of SOX9 than neural stem cells and mature astroglia and SOX9(low) GCP-like tumor cells constitute the bulk of both infant (Math1Cre: Ptch1(lox/lox)) and adult (Ptch1(LacZ/+)) SHH-MB mouse models. Human medulloblastoma single-cell RNA data analyses reveal three distinct SOX9 populations present in SHH-MB and noticeably absent in other medulloblastoma subgroups: SOX9(+)MATH1(+) (GCP), SOX9(+)GFAP(+) (astrocytes) and SOX9(+)MATH1(+)GFAP(+) (potential tumor-derived astrocytes). To functionally address whether SOX9 is required as a downstream effector of Hedgehog signaling in medulloblastoma tumor cells, we ablated Sox9 using a Math1Cre model system. Surprisingly, targeted ablation of Sox9 in GCPs (Math1Cre:Sox9(lox/lox)) revealed no overt phenotype and loss of Sox9 in SHH-MB (Math1Cre:Ptch1(lox/lox);Sox9(lox/lox)) does not affect tumor formation.
3.	Berg, Tracy J., et al. (author) The Irradiated Brain Microenvironment Supports Glioma Stemness and Survival via Astrocyte-Derived Transglutaminase 2 2021 In: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 81:8, s. 2101-2115 Journal article (peer-reviewed)abstract The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance. Following radiotherapy, recurrent gliomas form in an irradiated microenvironment. Here we report that astrocytes, when pre-irradiated, increase stemness and survival of cocultured glioma cells. Tumor-naive brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. Extracellular matrix derived from irradiated astrocytes were found to be a major driver of this phenotype and astrocyte-derived transglutaminase 2 (TGM2) was identified as a promoter of glioma stemness and radioresistance. TGM2 levels increased after radiation in vivo and in recurrent human glioma, and TGM2 inhibitors abrogated glioma stemness and survival. These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard-of-care radiotherapy by reducing stemness in glioma. Significance: These findings presented here indicate that radiotherapy can result in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence.
4.	Johansson, Patrik, et al. (author) A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma 2020 In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 32:2 Journal article (peer-reviewed)abstract Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells, We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.
5.	Bandopadhayay, Pratiti, et al. (author) BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma 2014 In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 20:4, s. 912-925 Journal article (peer-reviewed)abstract 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.
6.	Bolin, Sara, 1988-, et al. (author) Dormant SOX9-positive cells behind MYC-driven medulloblastoma recurrence Journal article (peer-reviewed)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.
7.	Borgenvik, Anna, 1987-, et al. (author) Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma 2022 In: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 82:24, s. 4586-4603 Journal article (peer-reviewed)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.
8.	Mohajershojai, Tabassom (author) Enhancing Cancer Treatment through Combination Therapies 2024 Doctoral thesis (other academic/artistic)abstract Cancer, a complex disease marked by uncontrolled cell growth, is typically treated with surgery, chemotherapy, radiation therapy and immunotherapy, which can induce significant side effects by affecting healthy tissues. Targeted radionuclide therapy (TRT), where cancer-targeting molecules are equipped with radionuclides to enable cancer-specific radiotherapy, shows promise for treating advanced cancers by addressing both metastatic relapse and heterogeneous tumors. Combining TRT with targeted therapies offers a promising shift towards more effective and less toxic treatments. This thesis focuses on synergistically enhancing the therapeutic efficacy of TRT or chemotherapy through combination strategies with novel drugs that modulate DNA damage and/or interact with the immune system.In Paper I, we investigated the combination treatment of the chemotherapy drug cisplatin with the heat shock protein 90 (HSP90) inhibitor onalespib in vitro, using ovarian and head and neck cancer cells. Our findings demonstrated that onalespib enhances the therapeutic effects of cisplatin, reducing colony formation and migration, increasing apoptosis, and decreasing DNA damage response (DDR). Key proteins such as ATM, DNA-PKcs, and γH2AX were shown to play crucial roles in the therapeutic efficacy of the combination treatments.In Papers II and III, we characterized the synergy between the novel radioconjugate, 177Lu-DOTA-M5A, and onalespib in gastrointestinal cancer models in vitro and in vivo. While 177Lu-DOTA-M5A exhibited significant cellular uptake and therapeutic efficacy as monotherapy in 3D tumor spheroids and xenografts. The combination exhibited the most pronounced synergistic growth inhibitory effects in both settings with no adverse effects observed in vivo. PARP1 was identified as playing a pivotal role in the therapeutic outcomes.In Paper IV, we explored combining 177Lu-DOTA-M5A with PD-1 immune checkpoint blockade in an immunocompetent transgenic mouse model. The radioconjugate demonstrated high tumor uptake and potent therapeutic effects as monotherapy without depleting immune cells within the tumor microenvironment, while PD-1 blockade further enhanced its efficacy by prolonging survival and suppressing tumor growth. CD8+ T cells and pro-inflammatory macrophages (M1) were critical for these therapeutic effects and no myelotoxicity was observed with any treatments.In conclusion, we have investigated various combination treatment approaches aimed at enhancing therapeutic efficacy while mitigating side effects and drug resistance. We have evaluated the feasibility, toxicity, and benefits of these combinations in preclinical settings with promising results, underscoring the potential of integrating TRT into combination therapy.Further investigation is warranted as an increasing number of TRT and combination therapies are entering clinical trials.
9.	Morgan, Daniel, et al. (author) Perturbation-based gene regulatory network inference to unravel oncogenic mechanisms 2020 In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1 Journal article (peer-reviewed)abstract The gene regulatory network (GRN) of human cells encodes mechanisms to ensure proper functioning. However, if this GRN is dysregulated, the cell may enter into a disease state such as cancer. Understanding the GRN as a system can therefore help identify novel mechanisms underlying disease, which can lead to new therapies. To deduce regulatory interactions relevant to cancer, we applied a recent computational inference framework to data from perturbation experiments in squamous carcinoma cell line A431. GRNs were inferred using several methods, and the false discovery rate was controlled by the NestBoot framework. We developed a novel approach to assess the predictiveness of inferred GRNs against validation data, despite the lack of a gold standard. The best GRN was significantly more predictive than the null model, both in cross-validated benchmarks and for an independent dataset of the same genes under a different perturbation design. The inferred GRN captures many known regulatory interactions central to cancer-relevant processes in addition to predicting many novel interactions, some of which were experimentally validated, thus providing mechanistic insights that are useful for future cancer research.
10.	Persson, Anders I, et al. (author) Non-stem cell origin for oligodendroglioma 2010 In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 18:6, s. 669-682 Journal article (peer-reviewed)abstract Malignant astrocytic brain tumors are among the most lethal cancers. Quiescent and therapy-resistant neural stem cell (NSC)-like cells in astrocytomas are likely to contribute to poor outcome. Malignant oligodendroglial brain tumors, in contrast, are therapy sensitive. Using magnetic resonance imaging (MRI) and detailed developmental analyses, we demonstrated that murine oligodendroglioma cells show characteristics of oligodendrocyte progenitor cells (OPCs) and are therapy sensitive, and that OPC rather than NSC markers enriched for tumor formation. MRI of human oligodendroglioma also suggested a white matter (WM) origin, with markers for OPCs rather than NSCs similarly enriching for tumor formation. Our results suggest that oligodendroglioma cells show hallmarks of OPCs, and that a progenitor rather than a NSC origin underlies improved prognosis in patients with this tumor.
11.	Roy, Ananya, et al. (author) Serglycin as a potential biomarker for glioma : association of serglycin expression, extent of mast cell recruitment and glioblastoma progression 2017 In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:15, s. 24815-24827 Journal article (peer-reviewed)abstract Serglycin is an intracellular proteoglycan with a unique ability to adopt highly divergent structures by glycosylation with variable types of glycosaminoglycans (GAGs) when expressed by different cell types. Serglycin is overexpressed in aggressive cancers suggesting its protumorigenic role. In this study, we explored the expression of serglycin in human glioma and its correlation with survival and immune cell infiltration. We demonstrate that serglycin is expressed in glioma and that increased expression predicts poor survival of patients. Analysis of serglycin expression in a large cohort of low- and high-grade human glioma samples reveals that its expression is grade dependent and is positively correlated with mast cell (MC) infiltration. Moreover, serglycin expression in patient-derived glioma cells is significantly increased upon MC co-culture. This is also accompanied by increased expression of CXCL12, CXCL10, as well as markers of cancer progression, including CD44, ZEB1 and vimentin.In conclusion, these findings indicate the importance of infiltrating MCs in glioma by modulating signaling cascades involving serglycin, CD44 and ZEB1. The present investigation reveals serglycin as a potential prognostic marker for glioma and demonstrates an association with the extent of MC recruitment and glioma progression, uncovering potential future therapeutic opportunities for patients.
12.	Susanto, Evelyn, et al. (author) Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells 2020 In: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 117:33, s. 20127-20138 Journal article (peer-reviewed)abstract Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using In-duced pluripotent stem (iPS) cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carry-ing a germline mutation in the sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Retransplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, en-hanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model, we identified LGALS1 to be a GLI target gene that is up-regulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we dem-onstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression and to identify putative targets.
13.	Swartling, Fredrik J., et al. (author) Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC 2012 In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 21:5, s. 601-613 Journal article (peer-reviewed)abstract The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally stabilized murine N-myc(T58A) into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem, and forebrain. Transplantation of N-myc(WT) NSCs was insufficient for tumor formation. N-myc(T58A) cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating Sonic Hedgehog (SHH) dependence and SHH independence, respectively. These differences were regulated in part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal.
14.	Swartling, Fredrik J., 1975-, et al. (author) Signals that regulate the oncogenic fate of neural stem cells and progenitors 2014 In: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 260, s. 56-68 Research review (peer-reviewed)abstract Brain tumors have frequently been associated with a neural stem cell (NSC) origin and contain stem-like tumor cells, so-called brain tumor stem cells (BTSCs) that share many features with normal NSCs. A stem cell state of BTSCs confers resistance to radiotherapy and treatment with alkylating agents. It is also a hallmark of aggressive brain tumors and is maintained by transcriptional networks that are also active in embryonic stem cells. Advances in reprogramming of somatic cells into induced pluripotent stem (iPS) cells have further identified genes that drive stemness. In this review, we will highlight the possible drivers of stemness in medulloblastoma and glioma, the most frequent types of primary malignant brain cancer in children and adults, respectively. Signals that drive expansion of developmentally defined neural precursor cells are also active in corresponding brain tumors. Transcriptomal subgroups of human medulloblastoma and glioma match features of NSCs but also more restricted progenitors. Lessons from genetically-engineered mouse (GEM) models show that temporally and regionally defined NSCs can give rise to distinct subgroups of medulloblastoma and glioma. We will further discuss how acquisition of stem cell features may drive brain tumorigenesis from a non-NSC origin. Genetic alterations, signaling pathways, and therapy-induced changes in the tumor microenvironment can drive reprogramming networks and induce stemness in brain tumors. Finally, we propose a model where dysregulation of microRNAs (miRNAs) that normally provide barriers against reprogramming plays an integral role in promoting stemness in brain tumors.
15.	Trieu, Kenneth G., et al. (author) Article Basal cell carcinomas acquire secondary mutations to overcome dormancy and progress from microscopic to macroscopic disease 2022 In: Cell Reports. - : Elsevier. - 2211-1247. ; 39:5 Journal article (peer-reviewed)abstract Basal cell carcinomas (BCCs) frequently possess immense mutational burdens; however, the functional significance of most of these mutations remains unclear. Here, we report that loss of Ptch1, the most common mutation that activates upstream Hedgehog (Hh) signaling, initiates the formation of nascent BCC-like tumors that eventually enter into a dormant state. However, rare tumors that overcome dormancy acquire the ability to hyperactivate downstream Hh signaling through a variety of mechanisms, including amplification of Gli1/2 and upregulation of Mycn. Furthermore, we demonstrate that MYCN overexpression promotes the progression of tumors induced by loss of Ptch1. These findings suggest that canonical mutations that activate upstream Hh signaling are necessary, but not sufficient, for BCC to fully progress. Rather, tumors likely acquire secondary mutations that further hyperactivate downstream Hh signaling in order to escape dormancy and enter a trajectory of uncontrolled expansion.
16.	Weishaupt, Holger, et al. (author) Novel cancer gene discovery using a forward genetic screen in RCAS-PDGFB-driven gliomas 2023 In: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 25:1, s. 97-107 Journal article (peer-reviewed)abstract Background Malignant gliomas, the most common malignant brain tumors in adults, represent a heterogeneous group of diseases with poor prognosis. Retroviruses can cause permanent genetic alterations that modify genes close to the viral integration site. Methods Here we describe the use of a high-throughput pipeline coupled to the commonly used tissue-specific retroviral RCAS-TVA mouse tumor model system. Utilizing next-generation sequencing, we show that retroviral integration sites can be reproducibly detected in malignant stem cell lines generated from RCAS-PDGFB-driven glioma biopsies. Results A large fraction of common integration sites contained genes that have been dysregulated or misexpressed in glioma. Others overlapped with loci identified in previous glioma-related forward genetic screens, but several novel putative cancer-causing genes were also found. Integrating retroviral tagging and clinical data, Ppfibp1 was highlighted as a frequently tagged novel glioma-causing gene. Retroviral integrations into the locus resulted in Ppfibp1 upregulation, and Ppfibp1-tagged cells generated tumors with shorter latency on orthotopic transplantation. In human gliomas, increased PPFIBP1 expression was significantly linked to poor prognosis and PDGF treatment resistance. Conclusions Altogether, the current study has demonstrated a novel approach to tagging glioma genes via forward genetics, validating previous results, and identifying PPFIBP1 as a putative oncogene in gliomagenesis.
17.	Xiong, Anqi, 1986-, et al. (author) Nuclear Receptor Binding Protein 2 Is Downregulated in Medulloblastoma, and Reduces Tumor Cell Survival upon Overexpression 2020 In: Cancers. - : MDPI AG. - 2072-6694. ; 12:6 Journal article (peer-reviewed)abstract Pseudokinases, comprising 10% of the human kinome, are emerging as regulators of canonical kinases and their functions are starting to be defined. We previously identified the pseudokinase Nuclear Receptor Binding Protein 2 (NRBP2) in a screen for genes regulated during neural differentiation. During mouse brain development,NRBP2is expressed in the cerebellum, and in the adult brain, mainly confined to specific neuronal populations. To study the role of NRBP2 in brain tumors, we stained a brain tumor tissue array for NRPB2, and find its expression to be low, or absent, in a majority of the tumors. This includes medulloblastoma (MB), a pediatric tumor of the cerebellum. Using database mining of published MB data sets, we also find that NRBP2 is expressed at a lower level in MB than in the normal cerebellum. Recent studies indicate that MB exhibits frequent epigenetic alternations and we therefore treated MB cell lines with drugs inhibiting DNA methylation or histone deacetylation, which leads to an upregulation of NRBP2 mRNA expression, showing that it is under epigenetic regulation in cultured MB cells. Furthermore, forced overexpression of NRBP2 in MB cell lines causes a dramatic decrease in cell numbers, increased cell death, impaired cell migration and inhibited cell invasion in vitro. Taken together, our data indicate that downregulation of NRBP2 may be a feature by which MB cells escape growth regulation.
18.	Bolin, Sara, et al. (author) A glial origin for medulloblastoma and inhibition of MYCN stabilization 2013 In: Cancer Research. - 0008-5472 .- 1538-7445. ; 73:8 Journal article (other academic/artistic)
19.	Bolin, Sara, 1988-, et al. (author) Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma 2018 In: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 37:21, s. 2850-2862 Journal article (peer-reviewed)abstract Medulloblastoma (MB) is the most common malignant brain tumor in children. MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively. Such combination treatment worked synergistically and caused cell cycle arrest as well as massive apoptosis. Immediate transcriptional changes from this combined MYC blockade were found using RNA-Seq profiling and showed remarkable similarities to changes in MYC target gene expression when MYCN was turned off with doxycycline in our MYCN-inducible animal model for Group 3 MB. In addition, the combination treatment significantly prolonged survival as compared to single-agent therapy in orthotopically transplanted human Group 3 MB with MYC amplifications. Our data suggest that dual inhibition of CDK2 and BET bromodomains can be a novel treatment approach for suppressing MYC-driven cancer.
20.	Borgenvik, Anna, et al. (author) CDK2 as a therapeutic target in MYC-driven medulloblastoma Other publication (other academic/artistic)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.
21.	Borgenvik, Anna, 1987- (author) MYC-driven Medulloblastoma : New Targeted Therapies and Mechanisms of Recurrence 2021 Doctoral thesis (other academic/artistic)abstract Medulloblastoma is the most common malignant brain tumor of childhood. It arises in the posterior fossa but presents with distinct histological and molecular features. Hence, medulloblastoma is divided into four molecular subgroups, WNT, SHH, Group 3, and Group 4. The overall 5-year survival is ~70% across subgroups but varies with high- and low-risk disease. Standard treatment of medulloblastoma consists of maximal safe tumor resection, radiotherapy, and adjuvant chemotherapy. Despite the rather high success rate of treatment for many patients it also comes with severe long-term debilitating side effects. MYC proteins are master regulators of gene expression often deregulated in cancer. MYC family members MYC and MYCN share similar roles and are found overexpressed or amplified in most medulloblastoma subgroups and correlate with a poor prognosis. Medulloblastoma dissemination and recurrence patterns differ between subgroups but are always associated with a poor prognosis. Recurrent medulloblastoma is not yet curable and will lead to death. In this thesis, we present the first transgenic mouse model of medulloblastoma recurrence and highlight the role of the transcription factor SOX9 in MYC-driven relapse mechanisms. By studying this recurrence model and matched primary-recurrent patient samples we propose a mechanism in which treatment-refractory and quiescent SOX9-positive cells in Group 3 medulloblastoma are necessary for tumor relapse, and how the recurrent tumors can be specifically treated with MGMT inhibitors and doxorubicin.In addition, we address efficient treatment options of primary MYC-driven medulloblastoma where BET bromodomain inhibition (JQ1) in combination with CDK2 inhibition (milciclib) of human Group 3 medulloblastoma will lead to apoptosis and prolonged survival of xenografted mice. This is explained by a dual hit on MYC transcriptional output and MYC protein stability exerted by JQ1 and milciclib respectively. Finally, in a different novel transgenic model of MYC-driven medulloblastoma, we show how temporal Cdk2 knock-out has no effect on MYC protein stability but slows down proliferation and prolongs survival of allografted mice. The need for better treatments and increased understanding of recurrent medulloblastoma is huge. To that end, this thesis focuses on and addresses novel treatments, the role of the cell cycle protein CDK2 as well as relapse mechanisms depending on dormant SOX9-positive cells in highly aggressive MYC-driven medulloblastoma.
22.	Borgenvik, Anna, et al. (author) Targeting MYCN in Molecularly Defined Malignant Brain Tumors 2021 In: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 10 Research review (peer-reviewed)abstract Misregulation of MYC genes, causing MYC overexpression or protein stabilization, is frequently found in malignant brain tumors highlighting their important roles as oncogenes. Brain tumors in children are the most lethal of all pediatric malignancies and the most common malignant primary adult brain tumor, glioblastoma, is still practically incurable. MYCN is one of three MYC family members and is crucial for normal brain development. It is associated with poor prognosis in many malignant pediatric brain tumor types and is focally amplified in specific adult brain tumors. Targeting MYCN has proved to be challenging due to its undruggable nature as a transcription factor and for its importance in regulating developmental programs also in healthy cells. In this review, we will discuss efforts made to circumvent the difficulty of targeting MYCN specifically by using direct or indirect measures to treat MYCN-driven brain tumors. We will further consider the mechanism of action of these measures and suggest which molecularly defined brain tumor patients that might benefit from MYCN-directed precision therapies.
23.	Čančer, Matko, 1989- (author) From Genes to Therapy : Modeling and Novel Therapeutic Strategies for Brain Tumors 2018 Doctoral thesis (other academic/artistic)abstract Medulloblastoma is the most common malignant pediatric brain tumor and is molecularly divided into four subgroups – WNT, SHH, Group 3 and Group 4. Two thirds of medulloblastoma patients survive, but survivors often suffer from severe, lifelong side-effects. The MYCN oncogene is deregulated in many medulloblastoma patients. Glioblastoma is the most common malignant brain tumor in adults, with a median survival of about one year. Glioblastoma is a highly heterogeneous tumor where targeted therapy has, so far, not been successful and most glioblastoma patients unfortunately die.In our first study we developed three novel humanized models of MYCN-driven SHH medulloblastoma. Histologically and molecularly these models closely resembled the infant class of SHH tumors. Further, we identified a set of clinically relevant genes that had prognostic significance among patients. mTOR signaling pathway was identified as a major contributor to invasion and dissemination, and we showed that mTOR specific inhibition suppressed migration and viability in vitro.In the second study we performed a forward genetic screen of retrovirally-induced murine PDGFB-driven gliomas and identified more than fifty candidate cancer-causing genes, of which many were mutated or deregulated in glioblastoma. One of the genes identified in this screen was PPFIBP1, found to be differentially expressed from obstructive retroviral integrations in PDGFB-driven glioma clones. Lower PPFIBP1 expression significantly decreased survival of mice and was found to be suppressed in glioblastoma patients. We propose PPFIBP1 to be a novel tumor suppressor gene that contributes to glioblastoma development.In the last study we used a panel of 19 patient-derived glioblastoma cell lines and identified a characteristic expression signature that predicts sensitivity to BET inhibition. BET inhibition resulted in apoptosis and senescence, cell cycle arrest and modulation of DNA damage response. The inhibitory effects of BET inhibition were further enhanced in combination with temozolomide, suggesting a promising future therapy for distinct subgroups of glioblastoma patients.This thesis addresses novel molecular findings in medulloblastoma and glioblastoma development, presents clinically relevant brain tumor models, and promising therapeutic approaches that can be used in future clinical trials in malignant pediatric and adult brain tumors.
24.	Čančer, Matko, et al. (author) Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy 2019 In: Cell Stem Cell. - : CELL PRESS. - 1934-5909 .- 1875-9777. ; 25:6, s. 855-870 Journal article (peer-reviewed)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.
25.	Colas, Kilian, et al. (author) Indolylbenzothiadiazoles as highly tunable fluorophores for imaging lipid droplet accumulation in astrocytes and glioblastoma cells 2021 In: RSC Advances. - : Royal Society of Chemistry. - 2046-2069. ; 11:39, s. 23960-23967 Journal article (peer-reviewed)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.

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