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Uhrbom, Lene
Publications (10 of 45) Show all publications
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
Kaffes, I., Szulzewsky, F., Chen, Z., Herting, C. J., Gabanic, B., Vega, J. E. V., . . . Hambardzumyan, D. (2019). Human Mesenchymal glioblastomas are characterized by an increased immune cell presence compared to Proneural and Classical tumors. Oncoimmunology, 8(11)
Open this publication in new window or tab >>Human Mesenchymal glioblastomas are characterized by an increased immune cell presence compared to Proneural and Classical tumors
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2019 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 8, no 11Article in journal (Refereed) Published
Abstract [en]

Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults, with a median survival of 14.6 months. Recent efforts have focused on identifying clinically relevant subgroups to improve our understanding of pathogenetic mechanisms and patient stratification. Concurrently, the role of immune cells in the tumor microenvironment has received increasing attention, especially T cells and tumor-associated macrophages (TAM). The latter are a mixed population of activated brain-resident microglia and infiltrating monocytes/monocyte-derived macrophages, both of which express ionized calcium-binding adapter molecule 1 (IBA1). This study investigated differences in immune cell subpopulations among distinct transcriptional subtypes of GBM. Human GBM samples were molecularly characterized and assigned to Proneural, Mesenchymal or Classical subtypes as defined by NanoString nCounter Technology. Subsequently, we performed and analyzed automated immunohistochemical stainings for TAM as well as specific T cell populations. The Mesenchymal subtype of GBM showed the highest presence of TAM, CD8(+), CD3(+) and FOXP3(+) T cells, as compared to Proneural and Classical subtypes. High expression levels of the TAM-related gene AIF1, which encodes the TAM-specific protein IBA1, correlated with a worse prognosis in Proneural GBM, but conferred a survival benefit in Mesenchymal tumors. We used our data to construct a mathematical model that could reliably identify Mesenchymal GBM with high sensitivity using a combination of the aforementioned cell-specific IHC markers. In conclusion, we demonstrated that molecularly distinct GBM subtypes are characterized by profound differences in the composition of their immune microenvironment, which could potentially help to identify tumors amenable to immunotherapy.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS INC, 2019
Keywords
Glioblastoma, microenvironment, subtype, macrophage, T cell, AIF1
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-396107 (URN)10.1080/2162402X.2019.1655360 (DOI)000483119600001 ()31646100 (PubMedID)
Funder
Swedish Cancer Society, 110363Swedish Cancer Society, 140385Swedish Cancer Society, 130500Swedish Research Council, 521-2013-3356German Research Foundation (DFG), SZ 350/1-1
Available from: 2019-11-01 Created: 2019-11-01 Last updated: 2019-11-01Bibliographically 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
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
Caja, L., Tzavlaki, K., Dadras, M. S., Tan, E.-J., Hatem, G., Maturi, N. P., . . . Moustakas, A. (2018). Snail regulates BMP and TGF beta pathways to control the differentiation status of glioma-initiating cells. Oncogene, 37(19), 2515-2531
Open this publication in new window or tab >>Snail regulates BMP and TGF beta pathways to control the differentiation status of glioma-initiating cells
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2018 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 37, no 19, p. 2515-2531Article in journal (Refereed) Published
Abstract [en]

Glioblastoma multiforme is a brain malignancy characterized by high heterogeneity, invasiveness, and resistance to current therapies, attributes related to the occurrence of glioma stem cells (GSCs). Transforming growth factor beta (TGF beta) promotes self-renewal and bone morphogenetic protein (BMP) induces differentiation of GSCs. BMP7 induces the transcription factor Snail to promote astrocytic differentiation in GSCs and suppress tumor growth in vivo. We demonstrate that Snail represses stemness in GSCs. Snail interacts with SMAD signaling mediators, generates a positive feedback loop of BMP signaling and transcriptionally represses the TGFB1 gene, decreasing TGF beta 1 signaling activity. Exogenous TGF beta 1 counteracts Snail function in vitro, and in vivo promotes proliferation and re-expression of Nestin, confirming the importance of TGFB1 gene repression by Snail. In conclusion, novel insight highlights mechanisms whereby Snail differentially regulates the activity of the opposing BMP and TGF beta pathways, thus promoting an astrocytic fate switch and repressing stemness in GSCs.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-355463 (URN)10.1038/s41388-018-0136-0 (DOI)000431873400005 ()29449696 (PubMedID)
Funder
Swedish Research Council, K2013-66X-14936-10-5Swedish Research Council, 2015-02757
Note

Andra och tredje författare delar andra författarskapet.

Available from: 2018-06-29 Created: 2018-06-29 Last updated: 2018-12-03Bibliographically approved
Jiang, Y., Marinescu, V. D., Xie, Y., Jarvius, M., Maturi, N. P., Haglund, C., . . . Uhrbom, L. (2017). Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin. Cell reports, 18(4), 977-990
Open this publication in new window or tab >>Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin
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2017 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 4, p. 977-990Article in journal (Refereed) Published
Abstract [en]

The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.

Keywords
cancer stem cell, cell of origin, central nervous system, drug response, glioblastoma, glioma, mouse model, neural stem cell, oligodendrocyte precursor cell, self-renewal
National Category
Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-319084 (URN)10.1016/j.celrep.2017.01.003 (DOI)000396474300013 ()28122246 (PubMedID)
Funder
Swedish Cancer Society, 110363 140385 150628Swedish Research Council, 90283201 C0259101 B0310101 E0331401Swedish Childhood Cancer Foundation, PROJ11/057 PR2014-0143Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2017-11-29Bibliographically approved
Roy, A., Libard, S., Weishaupt, H., Gustavsson, I., Uhrbom, L., Hesselager, G., . . . Tchougounova, E. (2017). Mast Cell Infiltration in Human Brain Metastases Modulates the Microenvironment and Contributes to the Metastatic Potential. Frontiers in Oncology, 7, Article ID 115.
Open this publication in new window or tab >>Mast Cell Infiltration in Human Brain Metastases Modulates the Microenvironment and Contributes to the Metastatic Potential
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2017 (English)In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 7, article id 115Article in journal (Refereed) Published
Abstract [en]

Metastatic brain tumors continue to be a clinical problem, despite new therapeutic advances in cancer treatment. Brain metastases (BMs) are among the most common mass lesions in the brain that are resistant to chemotherapies, have a very poor prognosis, and currently lack any efficient diagnostic tests. Predictions estimate that about 40% of lung and breast cancer patients will develop BM. Despite this, very little is known about the immunological and genetic aberrations that drive tumorigenesis in BM. In this study, we demonstrate the infiltration of mast cells (MCs) in a large cohort of human BM samples with different tissues of origin for primary cancer. We applied patient-derived BM cell models to the study of BM cell-MC interactions. BM cells when cocultured with MCs demonstrate enhanced growth and self-renewal capacity. Gene set enrichment analyses indicate increased expression of signal transduction and transmembrane proteins related genes in the cocultured BM cells. MCs exert their effect by release of mediators such as IL-8, IL-10, matrix metalloprotease 2, and vascular endothelial growth factor, thereby permitting metastasis. In conclusion, we provide evidence for a role of MCs in BM. Our findings indicate MCs' capability of modulating gene expression in BM cells and suggest that MCs can serve as a new target for drug development against metastases in the brain.

Keywords
IL-10, IL-8, brain metastases, mast cell, matrix metalloprotease 2, vascular endothelial growth factor
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-343584 (URN)10.3389/fonc.2017.00115 (DOI)000402502800001 ()28626727 (PubMedID)
Funder
Swedish Research Council, 522-2009-2452Swedish Cancer Society, CAN 2014/580
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-09-04Bibliographically approved
Niklasson, M., Maddalo, G., Sramkova, Z., Mutlu, E., Wee, S., Sekyrova, P., . . . Andäng, M. (2017). Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses. Cancer Research, 77(7), 1741-1752
Open this publication in new window or tab >>Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses
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2017 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 7, p. 1741-1752Article in journal (Refereed) Published
Abstract [en]

Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca(2+) and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstream signaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na(+), which compromised Na(+)-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-318377 (URN)10.1158/0008-5472.CAN-16-2274 (DOI)000398262400020 ()28087597 (PubMedID)
Funder
Swedish Childhood Cancer FoundationSwedish Cancer SocietySwedish Research CouncilThe Karolinska Institutet's Research FoundationEU, FP7, Seventh Framework Programme, XS-000158
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2017-06-30Bibliographically approved
Sreedharan, S., Maturi, N. P., Xie, Y., Sundström, A., Jarvius, M., Libard, S., . . . Uhrbom, L. (2017). Mouse models of pediatric supratentorial high-grade glioma reveal how cell-of-origin influences tumor development and phenotype. Cancer Research (3), 802-812
Open this publication in new window or tab >>Mouse models of pediatric supratentorial high-grade glioma reveal how cell-of-origin influences tumor development and phenotype
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2017 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, no 3, p. 802-812Article in journal (Refereed) Published
Abstract [en]

High-grade glioma (HGG) is a group of primary malignant brain tumors with dismal prognosis. Whereas adult HGG has been studied extensively, childhood HGG, a relatively rare disease, is less well-characterized. Here, we present two novel platelet-derived growth factor (PDGF)-driven mouse models of pediatric supratentorial HGG. Tumors developed from two different cells of origin reminiscent of neural stem cells (NSC) or oligodendrocyte precursor cells (OPC). Cross-species transcriptomics showed that both models are closely related to human pediatric HGG as compared with adult HGG. Furthermore, an NSC-like cell-of-origin enhanced tumor incidence, malignancy, and the ability of mouse glioma cells (GC) to be cultured under stem cell conditions as compared with an OPC-like cell. Functional analyses of cultured GC from these tumors showed that cells of NSC-like origin were more tumorigenic, had a higher rate of self-renewal and proliferation, and were more sensitive to a panel of cancer drugs compared with GC of a more differentiated origin. These two mouse models relevant to human pediatric supratentorial HGG propose an important role of the cell-of-origin for clinicopathologic features of this disease.

Keywords
pediatric high-grade glioma, glioblastoma, mouse model, cell of origin, glioma stem cell
National Category
Cell and Molecular Biology Clinical Laboratory Medicine
Research subject
Biomedical Laboratory Science; Pathology
Identifiers
urn:nbn:se:uu:diva-310215 (URN)10.1158/0008-5472.CAN-16-2482 (DOI)000393194400020 ()
Funder
Swedish Cancer SocietySwedish Childhood Cancer FoundationSwedish Research CouncilSwedish Society for Medical Research (SSMF)
Available from: 2016-12-13 Created: 2016-12-13 Last updated: 2019-04-02Bibliographically approved
Segerman, A., Niklasson, M., Haglund, C., Bergström, T., Jarvius, M., Xie, Y., . . . Westermark, B. (2016). Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition. Cell reports, 17(11), 2994-3009
Open this publication in new window or tab >>Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 17, no 11, p. 2994-3009Article in journal (Refereed) Published
Abstract [en]

Intratumoral heterogeneity is a hallmark of glioblastoma multiforme and thought to negatively affect treatment efficacy. Here, we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability among clones, including a range of responses to radiation and drugs. This widespread variability was observed as a continuumof multitherapy resistance phenotypes linked to a proneural-mesenchymal shift in the transcriptome. Multitherapy resistance was associated with a semi-stable cell state that was characterized by an altered DNA methylation pattern at promoter regions of mesenchymal master regulators and enhancers. The gradient of cell states within the GIC compartment constitutes a distinct form of heterogeneity. Our findings may open an avenue toward the development of new therapeutic rationales designed to reverse resistant cell states.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-314416 (URN)10.1016/j.celrep.2016.11.056 (DOI)000390894700019 ()
Funder
Knut and Alice Wallenberg Foundation, 2013.0280Swedish Cancer Society, 150670
Available from: 2017-02-08 Created: 2017-02-02 Last updated: 2017-11-29Bibliographically approved
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