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BETA
Johansson, Fredrik K.ORCID iD iconorcid.org/0000-0002-8460-4367
Alternative names
Publications (10 of 44) Show all publications
Hovestadt, V., Ayrault, O., Johansson Swartling, F. K., Robinson, G. W., Pfister, S. M. & Northcott, P. A. (2020). Medulloblastomics revisited: biological and clinical insights from thousands of patients. Nature Reviews. Cancer, 20(1), 42-56
Open this publication in new window or tab >>Medulloblastomics revisited: biological and clinical insights from thousands of patients
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2020 (English)In: Nature Reviews. Cancer, ISSN 1474-175X, E-ISSN 1474-1768, Vol. 20, no 1, p. 42-56Article, review/survey (Refereed) Published
Abstract [en]

Medulloblastoma, a malignant brain tumour primarily diagnosed during childhood, has recently been the focus of intensive molecular profiling efforts, profoundly advancing our understanding of biologically and clinically heterogeneous disease subgroups. Genomic, epigenomic, transcriptomic and proteomic landscapes have now been mapped for an unprecedented number of bulk samples from patients with medulloblastoma and, more recently, for single medulloblastoma cells. These efforts have provided pivotal new insights into the diverse molecular mechanisms presumed to drive tumour initiation, maintenance and recurrence across individual subgroups and subtypes. Translational opportunities stemming from this knowledge are continuing to evolve, providing a framework for improved diagnostic and therapeutic interventions. In this Review, we summarize recent advances derived from this continued molecular characterization of medulloblastoma and contextualize this progress towards the deployment of more effective, molecularly informed treatments for affected patients.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2020
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-402957 (URN)10.1038/s41568-019-0223-8 (DOI)000504714500007 ()31819232 (PubMedID)
Available from: 2020-01-22 Created: 2020-01-22 Last updated: 2020-01-22Bibliographically approved
Weishaupt, H., Johansson, P., Sundström, A., Lubovac-Pilav, Z., Olsson, B., Nelander, S. & Johansson Swartling, F. K. (2019). Batch-normalization of cerebellar and medulloblastoma gene expression datasets utilizing empirically defined negative control genes. Bioinformatics, 35(18), 3357-3364
Open this publication in new window or tab >>Batch-normalization of cerebellar and medulloblastoma gene expression datasets utilizing empirically defined negative control genes
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2019 (English)In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 35, no 18, p. 3357-3364Article in journal (Refereed) Published
Abstract [en]

Motivation: Medulloblastoma (MB) is a brain cancer predominantly arising in children. Roughly 70% of patients are cured today, but survivors often suffer from severe sequelae. MB has been extensively studied by molecular profiling, but often in small and scattered cohorts. To improve cure rates and reduce treatment side effects, accurate integration of such data to increase analytical power will be important, if not essential.

Results: We have integrated 23 transcription datasets, spanning 1350 MB and 291 normal brain samples. To remove batch effects, we combined the Removal of Unwanted Variation (RUV) method with a novel pipeline for determining empirical negative control genes and a panel of metrics to evaluate normalization performance. The documented approach enabled the removal of a majority of batch effects, producing a large-scale, integrative dataset of MB and cerebellar expression data. The proposed strategy will be broadly applicable for accurate integration of data and incorporation of normal reference samples for studies of various diseases. We hope that the integrated dataset will improve current research in the field of MB by allowing more large-scale gene expression analyses.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2019
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:uu:diva-395689 (URN)10.1093/bioinformatics/btz066 (DOI)000487327500019 ()30715209 (PubMedID)
Funder
EU, European Research Council, 640275Swedish Cancer SocietySwedish Research CouncilSwedish Childhood Cancer FoundationRagnar Söderbergs stiftelse
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved
Cancer, M., Drews, L. F., Bengtsson, J., Bolin, S., Rosén, G., Westermark, B., . . . Johansson, F. K. (2019). BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells. Cell Death and Disease, 10, Article ID 881.
Open this publication in new window or tab >>BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells
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2019 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 10, article id 881Article in journal (Refereed) Published
Abstract [en]

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN-elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Cancer and Oncology Cell Biology
Identifiers
urn:nbn:se:uu:diva-398423 (URN)10.1038/s41419-019-2120-1 (DOI)000497973200005 ()31754113 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish Society of MedicineRagnar Söderbergs stiftelseSwedish Childhood Cancer FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2019-12-06Bibliographically approved
Huang, M., Tailor, J., Zhen, Q., Gillmor, A. H., Miller, M. L., Weishaupt, H., . . . Weiss, W. A. (2019). Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis. Cell Stem Cell, 25(3), 433-+
Open this publication in new window or tab >>Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis
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2019 (English)In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 25, no 3, p. 433-+Article in journal (Refereed) Published
Abstract [en]

Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predis- posed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Cell and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:uu:diva-394687 (URN)10.1016/j.stem.2019.05.013 (DOI)000484603600014 ()31204176 (PubMedID)
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved
Čančer, M., Hutter, S., Holmberg Olausson, K., Rosén, G., Sundström, A., Tailor, J., . . . Johansson, F. K. (2019). Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy. Cell Stem Cell, 25(6), 855-870
Open this publication in new window or tab >>Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy
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2019 (English)In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 25, no 6, p. 855-870Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Cell Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-400664 (URN)10.1016/j.stem.2019.10.005 (DOI)000500942400013 ()31786016 (PubMedID)
Funder
EU, Horizon 2020, 640275Swedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Childhood Cancer FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceRagnar Söderbergs stiftelse
Available from: 2020-01-03 Created: 2020-01-03 Last updated: 2020-01-03Bibliographically approved
Xie, Y., Sundström, A., Maturi, N. P., Tan, E.-J., Marinescu, V. D., Jarvius, M., . . . Uhrbom, L. (2019). LGR5 promotes tumorigenicity and invasion of glioblastoma stem-like cells and is a potential therapeutic target for a subset of glioblastoma patients. Journal of Pathology, 247(2), 228-240
Open this publication in new window or tab >>LGR5 promotes tumorigenicity and invasion of glioblastoma stem-like cells and is a potential therapeutic target for a subset of glioblastoma patients
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2019 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 247, no 2, p. 228-240Article in journal (Refereed) Published
Abstract [en]

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor which lacks efficient treatment and predictive biomarkers. Expression of the epithelial stem cell marker Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) has been described in GBM, but its functional role has not been conclusively elucidated. Here, we have investigated the role of LGR5 in a large repository of patient-derived GBM stem cell (GSC) cultures. The consequences of LGR5 overexpression or depletion have been analyzed using in vitro and in vivo methods, which showed that, among those with highest LGR5 expression (LGR5(high)), there were two phenotypically distinct groups: one that was dependent on LGR5 for its malignant properties and another that was unaffected by changes in LGR5 expression. The LGR5-responding cultures could be identified by their significantly higher self-renewal capacity as measured by extreme limiting dilution assay (ELDA), and these LGR5(high)-ELDA(high) cultures were also significantly more malignant and invasive compared to the LGR5(high)-ELDA(low) cultures. This showed that LGR5 expression alone would not be a strict marker of LGR5 responsiveness. In a search for additional biomarkers, we identified LPAR4, CCND2, and OLIG2 that were significantly upregulated in LGR5-responsive GSC cultures, and we found that OLIG2 together with LGR5 were predictive of GSC radiation and drug response. Overall, we show that LGR5 regulates the malignant phenotype in a subset of patient-derived GSC cultures, which supports its potential as a predictive GBM biomarker. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
glioblastoma stem-like cells, LGR5, self-renewal, invasion, radiation response
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-376723 (URN)10.1002/path.5186 (DOI)000456331900009 ()30357839 (PubMedID)
Funder
Swedish Research Council, 2012-02591Swedish Cancer Society, 2012/4882015/656
Available from: 2019-02-11 Created: 2019-02-11 Last updated: 2019-02-11Bibliographically approved
Bolin, S., Borgenvik, A., Persson, C. U., Sundström, A., Qi, J., Bradner, J. E., . . . Swartling, F. J. (2018). Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma. Oncogene, 37(21), 2850-2862
Open this publication in new window or tab >>Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
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2018 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 37, no 21, p. 2850-2862Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-357024 (URN)10.1038/s41388-018-0135-1 (DOI)000432929800007 ()29511348 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-08-10 Created: 2018-08-10 Last updated: 2018-08-10Bibliographically approved
Weishaupt, H., Mainwaring, O., Hutter, S., Kalushkova, A., Jernberg Wiklund, H., Rosén, G. & Johansson, F. K. (2018). GMYC: A Novel Inducible Transgenic Model of Group 3 Medulloblastoma. Paper presented at 18th International Symposium on Pediatric Neuro-Oncology (ISPNO), JUN 30-JUL 03, 2018, Denver, CO. Neuro-Oncology, 20, 137-137
Open this publication in new window or tab >>GMYC: A Novel Inducible Transgenic Model of Group 3 Medulloblastoma
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2018 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, p. 137-137Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Oxford University Press, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-366679 (URN)10.1093/neuonc/noy059.487 (DOI)000438339000489 ()
Conference
18th International Symposium on Pediatric Neuro-Oncology (ISPNO), JUN 30-JUL 03, 2018, Denver, CO
Available from: 2018-11-27 Created: 2018-11-27 Last updated: 2018-11-27Bibliographically approved
Ferrucci, V., de Antonellis, P., Pennino, F. P., Asadzadeh, F., Virgilio, A., Montanaro, D., . . . Zollo, M. (2018). Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1–TGF-β–OTX2–SNAIL via PTEN inhibitio. Brain, 141(5), 1300-1319
Open this publication in new window or tab >>Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1–TGF-β–OTX2–SNAIL via PTEN inhibitio
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2018 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 141, no 5, p. 1300-1319Article in journal (Refereed) Published
Abstract [en]

Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common ‘non-synonymous homozygous’ deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.

Keywords
medulloblastoma, metastatic CNS tumour, molecular genetics, genetic network, oncology
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-356501 (URN)10.1093/brain/awy039 (DOI)000432177000017 ()29490009 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, EU-FP7-TUMIC-HEALTH-F2-2008-2016662
Available from: 2018-07-30 Created: 2018-07-30 Last updated: 2018-07-30Bibliographically approved
Wallmann, T., Zhang, X.-M., Wallerius, M., Bolin, S., Joly, A.-L., Sobocki, C., . . . Rolny, C. (2018). Microglia Induce PDGFRB Expression in Glioma Cells to Enhance Their Migratory Capacity. ISCIENCE, 9, 71-83
Open this publication in new window or tab >>Microglia Induce PDGFRB Expression in Glioma Cells to Enhance Their Migratory Capacity
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2018 (English)In: ISCIENCE, ISSN 2589-0042, Vol. 9, p. 71-83Article in journal (Refereed) Published
Abstract [en]

High-grade gliomas (HGGs) are the most aggressive and invasive primary brain tumors. The platelet-derived growth factor (PDGF) signaling pathway drives HGG progression, and enhanced expression of PDGF receptors (PDGFRs) is a well-established aberration in a subset of glioblastomas (GBMs). PDGFRA is expressed in glioma cells, whereas PDGFRB is mostly restricted to the glioma-associated stroma. Here we show that the spatial location of TAMMs correlates with the expansion of a subset of tumor cells that have acquired expression of PDGFRB in both mouse and human low-grade glioma and HCGs. Furthermore, M2-polarized microglia but not bone marrow (BM)-derived macrophages (BMDMs) induced PDGFRB expression in glioma cells and stimulated their migratory capacity. These findings illustrate a heterotypic cross-talk between microglia and glioma cells that may enhance the migratory and invasive capacity of the latter by inducing PDGFRB.

National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-373244 (URN)10.1016/j.isci.2018.10.011 (DOI)000454331400007 ()30384135 (PubMedID)
Funder
Swedish Cancer Society, 2016/825Swedish Cancer Society, CAN 2016/791Swedish Research Council, 2013-5982Swedish Childhood Cancer Foundation, NCP2015-0064Swedish Childhood Cancer Foundation, NC2014-0046Swedish Childhood Cancer Foundation, PR2014-0154Wallenberg Foundations
Available from: 2019-01-14 Created: 2019-01-14 Last updated: 2019-01-14Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-8460-4367

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