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BETA
Kastemar, Marianne
Alternative names
Publications (10 of 12) Show all publications
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
Xie, Y., Bergström, T., Jiang, Y., Johansson, P., Marinescu, V. D., Lindberg, N., . . . Uhrbom, L. (2015). The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes. EBioMedicine, 2(10), 1351-1363
Open this publication in new window or tab >>The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes
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2015 (English)In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 2, no 10, p. 1351-1363Article in journal (Refereed) Published
Abstract [en]

Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called gliomastem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional sub-types. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.

Keywords
Glioblastoma, Cell culture, Stem cell culture condition, Molecular subtype, Xenograft models
National Category
Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-274354 (URN)10.1016/j.ebiom.2015.08.026 (DOI)000365959700034 ()26629530 (PubMedID)
Note

De två sista författarna delar sistaförfattarskapet.

Available from: 2016-01-21 Created: 2016-01-21 Last updated: 2018-02-04Bibliographically approved
Lindberg, N., Jiang, Y., Xie, Y., Bolouri, H., Kastemar, M., Olofsson, T., . . . Uhrbom, L. (2014). Oncogenic Signaling Is Dominant to Cell of Origin and Dictates Astrocytic or Oligodendroglial Tumor Development from Oligodendrocyte Precursor Cells. Journal of Neuroscience, 34(44), 14644-14651
Open this publication in new window or tab >>Oncogenic Signaling Is Dominant to Cell of Origin and Dictates Astrocytic or Oligodendroglial Tumor Development from Oligodendrocyte Precursor Cells
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2014 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 44, p. 14644-14651Article in journal (Refereed) Published
Abstract [en]

Stem cells, believed to be the cellular origin of glioma, are able to generate gliomas, according to experimental studies. Here we investigated the potential and circumstances of more differentiated cells to generate glioma development. We and others have shown that oligodendrocyte precursor cells (OPCs) can also be the cell of origin for experimental oligodendroglial tumors. However, the question of whether OPCs have the capacity to initiate astrocytic gliomas remains unanswered. Astrocytic and oligodendroglial tumors represent the two most common groups of glioma and have been considered as distinct disease groups with putatively different origins. Here we show that mouse OPCs can give rise to both types of glioma given the right circumstances. We analyzed tumors induced by K-RAS and AKT and compared them to oligodendroglial platelet-derived growth factor B-induced tumors in Ctv-a mice with targeted deletions of Cdkn2a (p16(Ink4a-/-), p19(Arf-/-), Cdkn2a(-/-)). Our results showed that glioma can originate from OPCs through overexpression of K-RAS and AKT when combined with p19(Arf) loss, and these tumors displayed an astrocytic histology and high expression of astrocytic markers. We argue that OPC shave the potential to develop both astrocytic and oligodendroglial tumors given loss of p19(Arf), and that oncogenic signaling is dominant to cell of origin in determining glioma phenotype. Our mouse data are supported by the fact that human astrocytoma and oligodendroglioma display a high degree of overlap in global gene expression with no clear distinctions between the two diagnoses.

Keywords
astrocytoma, cell of origin, glioma, low-grade glioma, oligodendroglioma, PDGF
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-240010 (URN)10.1523/JNEUROSCI.2977-14.2014 (DOI)000345220100014 ()25355217 (PubMedID)
Available from: 2015-01-05 Created: 2015-01-05 Last updated: 2018-01-11Bibliographically approved
Caglayan, D., Lundin, E., Kastemar, M., Westermark, B. & Ferletta, M. (2013). Sox21 inhibits glioma progression in vivo by forming complexes with Sox2 and stimulating aberrant differentiation. International Journal of Cancer, 133(6), 1345-1356
Open this publication in new window or tab >>Sox21 inhibits glioma progression in vivo by forming complexes with Sox2 and stimulating aberrant differentiation
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2013 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 6, p. 1345-1356Article in journal (Refereed) Published
Abstract [en]

Sox2 is a transcription factor in neural stem cells and keeps the cells immature and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas. What's new? Glioma formation is driven by brain tumor-initiating cells with stem cell-like properties. Here the authors show for the first time that the transcription factor Sox21 can act as a suppressor gene in gliomagenesis. Induced expression of Sox21 in human glioma cells results in reduced tumor growth and prolonged survival of xenotranplanted mice. Sox21 reduces the stem-cell like properties of the tumor cells, leading to abnormal differentiation, induced apoptosis, and decreased proliferation. The results point to a shift in balance between the counteracting and widely distributed Sox2 and Sox21, revealing the Sox2/Sox21 axis as a target for novel therapy of gliomas.

Keywords
brain tumors, glioma, Sox2, Sox21, S100
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-204812 (URN)10.1002/ijc.28147 (DOI)000321436300008 ()
Available from: 2013-08-13 Created: 2013-08-12 Last updated: 2017-12-06Bibliographically approved
Caglayan, D., Lundin, E., Kastemar, M., Westermark, B. & Ferletta, M. (2013). Sox21 inhibits glioma progression in vivo by reducing Sox2 and stimulating aberrant differentiation. International Journal of Cancer, 133(6), 1345-1356
Open this publication in new window or tab >>Sox21 inhibits glioma progression in vivo by reducing Sox2 and stimulating aberrant differentiation
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2013 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 6, p. 1345-1356Article in journal (Refereed) Published
Abstract [en]

Sox2 is a transcription factor in neural stem cells and keeps the cells immature and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100β, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas.

Keywords
brain tumors, glioma, Sox2, Sox21, S100
National Category
Medical and Health Sciences Cell and Molecular Biology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-182943 (URN)10.1002/ijc.28147 (DOI)
Available from: 2012-10-19 Created: 2012-10-19 Last updated: 2018-01-12Bibliographically approved
Ferletta, M., Caglayan, D., Lundin, E., Kastemar, M. & Westermark, B. (2012). Induced Expression of Sox21 Inhibits Glioma Progression in Vivo by Stimulating Aberrant Differentiation. Paper presented at 22nd Biennial Congress of the European-Association-for-Cancer-Research, JUL 07-10, 2012, Barcelona, SPAIN. European Journal of Cancer, 48(S5), S95-S95
Open this publication in new window or tab >>Induced Expression of Sox21 Inhibits Glioma Progression in Vivo by Stimulating Aberrant Differentiation
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2012 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, no S5, p. S95-S95Article in journal, Meeting abstract (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-194479 (URN)10.1016/S0959-8049(12)71078-X (DOI)000313036500361 ()
Conference
22nd Biennial Congress of the European-Association-for-Cancer-Research, JUL 07-10, 2012, Barcelona, SPAIN
Available from: 2013-02-15 Created: 2013-02-14 Last updated: 2017-12-06Bibliographically approved
Põlajeva, J., Sjösten, A. M., Lager, N., Kastemar, M., Waern, I., Alafuzoff, I., . . . Tchougounova, E. (2011). Mast Cell Accumulation in Glioblastoma with a Potential Role for Stem Cell Factor and Chemokine CXCL12. PLoS ONE, 6(9), Article ID e25222.
Open this publication in new window or tab >>Mast Cell Accumulation in Glioblastoma with a Potential Role for Stem Cell Factor and Chemokine CXCL12
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, article id e25222Article in journal (Refereed) Published
Abstract [en]

Glioblastoma multiforme (GBM) is the most common and malignant form of glioma with high mortality and no cure. Many human cancers maintain a complex inflammatory program triggering rapid recruitment of inflammatory cells, including mast cells (MCs), to the tumor site. However, the potential contribution of MCs in glioma has not been addressed previously. Here we report for the first time that MCs infiltrate KRas+Akt-induced gliomas, using the RCAS/TV-a system, where KRas and Akt are transduced by RCAS into the brains of neonatal Gtv-a- or Ntv-a transgenic mice lacking Ink4a or Arf. The most abundant MC infiltration was observed in high-grade gliomas of Arf-/- mice. MC accumulation could be localized to the vicinity of glioma-associated vessels but also within the tumor mass. Importantly, proliferating MCs were detected, suggesting that the MC accumulation was caused by local expansion of the MC population. In line with these findings, strong expression of stem cell factor (SCF), i.e. the main MC growth factor, was detected, in particular around tumor blood vessels. Further, glioma cells expressed the MC chemotaxin CXCL12 and MCs expressed the corresponding receptor, i.e. CXCR4, suggesting that MCs could be attracted to the tumor through the CXCL12/CXCR4 axis. Supporting a role for MCs in glioma, strong MC infiltration was detected in human glioma, where GBMs contained significantly higher MC numbers than grade II tumors did. Moreover, human GBMs were positive for CXCL12 and the infiltrating MCs were positive for CXCR4. In conclusion, we provide the first evidence for a role for MCs in glioma.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-159545 (URN)10.1371/journal.pone.0025222 (DOI)000295257900060 ()21949886 (PubMedID)
Available from: 2011-10-04 Created: 2011-10-04 Last updated: 2017-12-08Bibliographically approved
Lindberg, N., Kastemar, M., Olofsson, T., Smits, A. & Uhrbom, L. (2009). Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma. Oncogene, 28(23), 2266-2275
Open this publication in new window or tab >>Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma
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2009 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 28, no 23, p. 2266-2275Article in journal (Refereed) Published
Abstract [en]

Gliomas are primary brain tumors mainly affecting adults. The cellular origin is unknown. The recent identification of tumor-initiating cells in glioma, which share many similarities with normal neural stem cells, has suggested the cell of origin to be a transformed neural stem cell. In previous studies, using the RCAS/tv-a mouse model, platelet-derived growth factor B (PDGF-B)-induced gliomas have been generated from nestin or glial fibrillary acidic protein-expressing cells, markers of neural stem cells. To investigate if committed glial progenitor cells could be the cell of origin for glioma, we generated the Ctv-a mouse where tumor induction would be restricted to myelinating oligodendrocyte progenitor cells (OPCs) expressing 2',3'-cyclic nucleotide 3'-phosphodiesterase. We showed that PDGF-B transfer to OPCs could induce gliomas with an incidence of 33%. The majority of tumors resembled human WHO grade II oligodendroglioma based on close similarities in histopathology and expression of cellular markers. Thus, with the Ctv-a mouse we have showed that the cell of origin for glioma may be a committed glial progenitor cell.

Keywords
glioma, cell of origin, neural stem cell, oligodendrocyte progenitor cell, glial cell, PDGF
National Category
Medical and Health Sciences
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-109379 (URN)10.1038/onc.2009.76 (DOI)000266886300003 ()19421151 (PubMedID)
Available from: 2009-10-14 Created: 2009-10-14 Last updated: 2017-12-12Bibliographically approved
Tchougounova, E., Kastemar, M., Bråsäter, D., Holland, E. C., Westermark, B. & Uhrbom, L. (2007). Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma. Oncogene, 26(43), 6289-6296
Open this publication in new window or tab >>Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma
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2007 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 26, no 43, p. 6289-6296Article in journal (Refereed) Published
Abstract [en]

In a subset of gliomas, the platelet-derived growth factor (PDGF) signaling pathway is perturbed. This is usually an early event occurring in low-grade tumors. In high-grade gliomas, the subsequent loss of the INK4a-ARF locus is one of the most common mutations. Here, we dissected the separate roles of Ink4a and Arf in PDGFB-induced oligodendroglioma development in mice. We found that there were differential functions of the two tumor suppressor genes. In tumors induced from astrocytes, both Ink4a-loss and Arf-loss caused a significantly increased incidence compared to wild-type mice. In tumors induced from glial progenitor cells there was a slight increase in tumor incidence in Ink4a-/- mice and Ink4a-Arf-/- mice compared to wild-type mice. In both progenitor cells and astrocytes, Arf-loss caused a pronounced increase in tumor malignancy compared to Ink4a-loss. Hence, Ink4a-loss contributed to tumor initiation from astrocytes and Arf-loss caused tumor progression from both glial progenitor cells and astrocytes. Results from in vitro studies on primary brain cell cultures suggested that the PDGFB-induced activation of the mitogen-activated protein kinase pathway via extracellular signal-regulated kinase was involved in the initiation of low-grade oligodendrogliomas and that the additional loss of Arf may contribute to tumor progression through increased levels of cyclin D1 and a phosphoinositide 3-kinase-dependent activation of p70 ribosomal S6 kinase causing a strong proliferative response of tumor cells.

Keywords
oligodendroglioma, PDGF, mouse model, Ink4a, Arf, p70S6K
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-10833 (URN)10.1038/sj.onc.1210455 (DOI)000249583300005 ()17438529 (PubMedID)
Available from: 2007-04-25 Created: 2007-04-25 Last updated: 2017-12-11Bibliographically approved
Hägerstrand, D., Hesselager, G., Achterberg, S., Wickenberg Bolin, U., Kowanetz, M., Kastemar, M., . . . Östman, A. (2006). Characterization of an imatinib-sensitive subset of high-grade human glioma cultures. Oncogene, 25(35), 4913-4922
Open this publication in new window or tab >>Characterization of an imatinib-sensitive subset of high-grade human glioma cultures
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2006 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 25, no 35, p. 4913-4922Article in journal (Refereed) Published
Abstract [en]

High-grade gliomas, including glioblastomas, are malignant brain tumors for which improved treatment is urgently needed. Genetic studies have demonstrated the existence of biologically distinct subsets. Preliminary studies have indicated that platelet-derived growth factor (PDGF) receptor signaling contributes to the growth of some of these tumors. In this study, human high-grade glioma primary cultures were analysed for sensitivity to treatment with the PDGF receptor inhibitor imatinib/Glivec/Gleevec/STI571. Six out of 15 cultures displayed more than 40% growth inhibition after imatinib treatment, whereas seven cultures showed less than 20% growth inhibition. In the sensitive cultures, apoptosis contributed to growth inhibition. Platelet-derived growth factor receptor status correlated with imatinib sensitivity. Supervised analyses of gene expression profiles and real-time PCR analyses identified expression of the chemokine CXCL12/SDF-1 (stromal cell-derived factor 1) as a predictor of imatinib sensitivity. Exogenous addition of CXCL12 to imatinib-insensitive cultures conferred some imatinib sensitivity. Finally, coregulation of CXCL12 and PDGF alpha-receptor was observed in glioblastoma biopsies. We have thus defined the characteristics of a novel imatinib-sensitive subset of glioma cultures, and provided evidence for a functional relationship between imatinib sensitivity and chemokine signaling. These findings will assist in the design and evaluation of clinical trials exploring therapeutic effects of imatinib on malignant brain tumors.

Keywords
PDGF receptor, imatinib, CXCL12, glioblastoma multiforme, microarray
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-81649 (URN)10.1038/sj.onc.1209497 (DOI)000239687100009 ()16547494 (PubMedID)
Available from: 2007-04-05 Created: 2007-04-05 Last updated: 2017-12-14Bibliographically approved
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