| 1. |
- Babacic, Haris, et al.
(författare)
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Glioblastoma stem cells express non-canonical proteins and exclusive mesenchymal-like or non-mesenchymal-like protein signatures
- 2023
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Ingår i: Molecular Oncology. - : John Wiley & Sons. - 1574-7891 .- 1878-0261. ; 17:2, s. 238-260
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) cancer stem cells (GSCs) contribute to GBM's origin, recurrence, and resistance to treatment. However, the understanding of how mRNA expression patterns of GBM subtypes are reflected at global proteome level in GSCs is limited. To characterize protein expression in GSCs, we performed in-depth proteogenomic analysis of patient-derived GSCs by RNA-sequencing and mass-spectrometry. We quantified > 10 000 proteins in two independent GSC panels and propose a GSC-associated proteomic signature characterizing two distinct phenotypic conditions; one defined by proteins upregulated in proneural and classical GSCs (GPC-like), and another by proteins upregulated in mesenchymal GSCs (GM-like). The GM-like protein set in GBM tissue was associated with necrosis, recurrence, and worse overall survival. Through proteogenomics, we discovered 252 non-canonical peptides in the GSCs, i.e., protein sequences that are variant or derive from genome regions previously considered non-protein-coding, including variants of the heterogeneous ribonucleoproteins implicated in RNA splicing. In summary, GSCs express two protein sets that have an inverse association with clinical outcomes in GBM. The discovery of non-canonical protein sequences questions existing gene models and pinpoints new protein targets for research in GBM.
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| 2. |
- Babateen, Omar, et al.
(författare)
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Etomidate, propofol and diazepam potentiate GABA-evoked GABAA currents in a cell line derived from Human glioblastoma
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 748, s. 101-107
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Tidskriftsartikel (refereegranskat)abstract
- GABAA receptors are pentameric chloride ion channels that are opened by GABA. We have screened a cell line derived from human glioblastoma, U3047MG, for expression of GABAA receptor subunit isoforms and formation of functional ion channels. We identified GABAA receptors subunit α2, α3, α5, β1, β2, β3, δ, γ3, π, and θ mRNAs in the U3047MG cell line. Whole-cell GABA-activated currents were recorded and the half-maximal concentration (EC50) for the GABA-activated current was 36μM. The currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and enhanced by the benzodiazepine diazepam (1μM) and the general anesthetics etomidate and propofol (50μM). In line with the expressed GABAA receptors containing at least the α3β3θ subunits, the receptors were highly sensitive to etomidate (EC50=55nM). Immunocytochemistry identified expression of the α3 and β3 subunit proteins. Our results show that the GABAA receptors in the glial cell line are functional and are modulated by classical GABAA receptor drugs. We propose that the U3047MG cell line may be used as a model system to study GABAA receptors function and pharmacology in glial cells.
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| 3. |
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| 4. |
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| 5. |
- Boije, Maria
(författare)
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Investigations of Proneural Glioblastoma to Identify Novel Therapeutic Targets
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Malignant glioma is a highly lethal and destructive disease with no proper cure. We have investigated some of the hallmarks of cancer in connection to glioma and found ways to disrupt these and prevent tumor growth. The work is done within the context of a glioma subtype distinguished by activation of PDGF signaling termed the proneural subtype. In two of the studies we have investigated mechanisms regulating the glioma cells themselves, and in the other two we have focused on the tumor stroma. In the first study, glioma-initiating cells were isolated in defined serum free culture medium from PDGF-B driven murine glioma and shown to be independent of EGF and FGF2 for self-renewal and proliferation. When cultured in serum the GICs displayed an aberrant differentiation pattern that was reversible. Specific depletion of the transduced PDGF-B caused a loss of self-renewal and tumorigenicity and induced oligodendrocyte differentiation. The transcription factor S-SOX5 has previously been shown to have a tumor suppressive effect on PDGF-B induced murine glioma, and to induce cellular senescence in PDGF-B stimulated cells in vitro. We found that S-SOX5 had a negative effect on proliferation of newly established human glioma cells cultured under stem cell conditions. We also revealed a connection between alterations causing up-regulation of SOX5 with the proneural subgroup and a tendency towards co-occurrence with PDGFRA alterations. Angiogenesis, the formation of new blood vessels from existing ones, is an important hallmark for glioma malignancy. We found that the anti-angiogenic protein HRG had a negative effect on glioma progression in PDGF-B induced experimental tumors and that HRG was able to completely prevent formation of glioblastomas. Subsequently it was shown that HRG could skew pro-tumorigenic tumor associated macrophages into an anti-tumorigenic phenotype. Stromal cells had not previously been fully investigated in gliomas. We observed a correlation between tumor malignancy and increased numbers of tumor-associated macrophages as well as pericytes in PDGF-B induced gliomas. There was also a correlation between tumor grade and vessel functionality that had not previously been shown. Our results offer further understanding of gliomagenesis and present possible future therapies.
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| 6. |
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| 7. |
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| 8. |
- Caja, Laia, et al.
(författare)
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Snail regulates BMP and TGF beta pathways to control the differentiation status of glioma-initiating cells
- 2018
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 37:19, s. 2515-2531
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
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| 10. |
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| 11. |
- Cancer, Matko, et al.
(författare)
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BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells
- 2019
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Ingår i: Cell Death and Disease. - : NATURE PUBLISHING GROUP. - 2041-4889. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 12. |
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| 13. |
- Čančer, Matko, 1989-
(författare)
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From Genes to Therapy : Modeling and Novel Therapeutic Strategies for Brain Tumors
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 14. |
- Dalmo, Erika
(författare)
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Glioblastoma heterogeneity and plasticity : Investigating the roles of BMP4 and SOX2
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The malignant primary brain tumor glioblastoma has a dismal prognosis and is distinguished by its heterogeneous character. Current treatment with surgical resection, radiotherapy and adjuvant chemotherapy with the alkylating agent temozolomide does not provide a cure, but simply prolongs survival by a few months. Since the tumors recur, cells remaining after treatment can act as cancer stem cells and are able to reform the tumor. This thesis provides insights into glioblastoma heterogeneity and how dominant transcriptional programs have a substantial impact on glioblastoma cell responses to altered levels of the intrinsic proteins BMP4 and SOX2. SOX2 has a role as a stem cell transcription factor in the normal nervous system and in glioblastoma, while BMP4 acts as a cue for astrocytic differentiation during normal nervous system development. As a response to BMP4, we find a wide spectrum of growth-inhibition across 40 human glioblastoma cell lines and correlate the extent of the response with baseline gene expression in the cells. We discover a connection between high SOX2 expression and a more pronounced growth-inhibitory response and establish a causative relationship between SOX2 downregulation and reduced proliferation in BMP4-responsive cell lines. We also find how BMP4 can induce a senescence-like phenotype in glioblastoma and connect it to a mesenchymal phenotype on a proneural-mesenchymal scale by investigating clonally derived cultures from the same tumor. Through elimination of senescent cells by senolytic treatment and generation p21-knockout cells we also establish a p21-dependence for BMP4-induced senescence.Studies on cellular organization identify a hierarchical cell-state pattern which the cells move through during culture and show that external perturbations (here by BMP4 and temozolomide) alter this hierarchy, demonstrating a substantial cellular plasticity.Also, we establish a strategy to eradicate endogenous SOX2 with the inducible exogenous SOX2-system present, demonstrating that SOX2 is not an essential transcription factor in all glioblastomas. In summary, this thesis highlights several aspects of inter- and intratumoral heterogeneity as well as cellular plasticity, providing valuable insights that could help guide the glioblastoma community in the pursuit of more effective therapies against glioblastoma.
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| 15. |
- Dalmo, Erika, et al.
(författare)
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Targeting SOX2 in glioblastoma cells reveals heterogeneity in SOX2 dependency
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma (GBM) is a lethal disease with no curative treatment. SOX2 is a stem cell transcription factor which is widely expressed across human GBM tumors. Downregulation of SOX2 inhibits tumor formation and its depletion leads to a complete stop of cell proliferation. Despite its known important role in GBM, there is a lack of SOX2 overexpression studies in human GBM cells cultured under stem cell conditions. Previous work in our lab suggests that SOX2 levels need to be precisely maintained for GBM cells to thrive. In this project, we have investigated how altered SOX2 expression affects primary human GBM lines. We found that elevated SOX2 expression inhibited proliferation in a dose-dependent manner in three out of four GBM cell lines. Global gene expression in the resistant line was shifted towards that of the proliferation-inhibited lines upon SOX2 induction. However, SOX2 induction also led to an increase in a GBM stem cell injury response phenotype, which was not present in proliferation-inhibited lines. Furthermore, CRISPR/Cas9-mediated SOX2 knockout revealed a SOX2 independence in the resistant cell line, where SOX2-negative cells could be propagated both in vitro and in vivo.
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| 16. |
- Damhofer, Helene, et al.
(författare)
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TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers
- 2024
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Ingår i: Cell Death and Disease. - : Springer Nature. - 2041-4889. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Poor survival and lack of treatment response in glioblastoma (GBM) is attributed to the persistence of glioma stem cells (GSCs). To identify novel therapeutic approaches, we performed CRISPR/Cas9 knockout screens and discovered TGFβ activated kinase (TAK1) as a selective survival factor in a significant fraction of GSCs. Loss of TAK1 kinase activity results in RIPK1-dependent apoptosis via Caspase-8/FADD complex activation, dependent on autocrine TNFα ligand production and constitutive TNFR signaling. We identify a transcriptional signature associated with immune activation and the mesenchymal GBM subtype to be a characteristic of cancer cells sensitive to TAK1 perturbation and employ this signature to accurately predict sensitivity to the TAK1 kinase inhibitor HS-276. In addition, exposure to pro-inflammatory cytokines IFN gamma and TNFα can sensitize resistant GSCs to TAK1 inhibition. Our findings reveal dependency on TAK1 kinase activity as a novel vulnerability in immune-activated cancers, including mesenchymal GBMs that can be exploited therapeutically.
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| 17. |
- Ferletta, Maria, 1973-, et al.
(författare)
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Forced expression of Sox21 inhibits Sox2 and induces apoptosis in human glioma cells
- 2011
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 129:1, s. 45-60
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Tidskriftsartikel (refereegranskat)abstract
- Numerous studies support a role for Sox2 to keep stem cells and progenitor cells in an immature and proliferative state. Coexpression of Sox2 and GFAP has been found in regions of the adult brain where neural stem cells are present and in human glioma cells. In our study, we have investigated the roles of Sox2 and its counteracting partner Sox21 in human glioma cells. We show for the first time that Sox21 is expressed in both primary glioblastoma and in human glioma cell lines. We found that coexpression of Sox2, GFAP and Sox21 was mutually exclusive with expression of fibronectin. Our result suggests that glioma consists of at least two different cell populations: Sox2+/GFAP+/Sox21+/FN- and Sox2-/GFAP-/Sox21-/FN1+. Reduction of Sox2 expression by using siRNA against Sox2 or by overexpressing Sox21 using a tetracyclineregulated expression system (Tet-on) caused decreased GFAP expression and a reduction in cell number due to induction of apoptosis. We suggest that Sox21 can negatively regulate Sox2 in glioma. Our findings imply that Sox2 and Sox21 may be interesting targets for the development of novel glioma therapy.
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| 18. |
- Ferletta, Maria, et al.
(författare)
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Sox10 Has a Broad Expression Pattern in Gliomas and Enhances Platelet-Derived Growth Factor-B–Induced Gliomagenesis
- 2007
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 5:9, s. 891-897
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Tidskriftsartikel (refereegranskat)abstract
- In a previously published insertional mutagenesis screen for candidate brain tumor genes in the mouse using a Moloney mouse leukemia virus encoding platelet-derived growth factor (PDGF)-B, the Sox10 gene was tagged in five independent tumors. The proviral integrations suggest an enhancer effect on Sox10. All Moloney murine leukemia virus/PDGFB tumors had a high protein expression of Sox10 independently of malignant grade or tumor type. To investigate the role of Sox10 in gliomagenesis, we used the RCAS/tv-a mouse model in which the expression of retroviral-encoded genes can be directed to glial progenitor cells (Ntv-a mice). Both Ntv-a transgenic mice, wild-type, and Ntv-a p19Arf null mice were injected with RCAS-SOX10 alone or in combination with RCAS-PDGFB. Infection with RCAS-SOX10 alone did not induce any gliomas. Combined infection of RCAS-SOX10 and RCAS-PDGFB in wild-type Ntv-a mice yielded a tumor frequency of 12%, and in Ntv-a Arf−/− mice the tumor frequency was 30%. This indicates that Sox10 alone is not sufficient to induce gliomagenesis but acts synergistically with PDGFB in glioma development. All induced tumors displayed characteristics of PNET-like structures and oligodendroglioma. The tumors had a strong and widely distributed expression of Sox10 and PDGFR-α. We investigated the expression of Sox10 in other human tumors and in a number of gliomas. The Sox10 expression was restricted to gliomas and melanomas. All glioma types expressed Sox10, and tumors of low-grade glioma had a much broader distribution of Sox10 compared with high-grade gliomas.
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| 19. |
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| 20. |
- Ilkhanizadeh, Shirin, et al.
(författare)
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Live Detection of Neural Progenitors and Glioblastoma Cells by an Oligothiophene Derivative
- 2023
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Ingår i: ACS Applied Bio Materials. - : American Chemical Society (ACS). - 2576-6422. ; 6:9, s. 3790-3797
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Tidskriftsartikel (refereegranskat)abstract
- There is an urgent need for simple and non-invasive identification of live neural stem/progenitor cells (NSPCs) in the developing and adult brain as well as in disease, such as in brain tumors, due to the potential clinical importance in prognosis, diagnosis, and treatment of diseases of the nervous system. Here, we report a luminescent conjugated oligothiophene (LCO), named p-HTMI, for non-invasive and non-amplified real-time detection of live human patient-derived glioblastoma (GBM) stem cell-like cells and NSPCs. While p-HTMI stained only a small fraction of other cell types investigated, the mere addition of p-HTMI to the cell culture resulted in efficient detection of NSPCs or GBM cells from rodents and humans within minutes. p-HTMI is functionalized with a methylated imidazole moiety resembling the side chain of histidine/histamine, and non-methylated analogues were not functional. Cell sorting experiments of human GBM cells demonstrated that p-HTMI labeled the same cell population as CD271, a proposed marker for stem cell-like cells and rapidly migrating cells in glioblastoma. Our results suggest that the LCO p-HTMI is a versatile tool for immediate and selective detection of neural and glioma stem and progenitor cells.
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| 21. |
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| 22. |
- Jiang, Yiwen, et al.
(författare)
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Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 18:4, s. 977-990
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 23. |
- Jiang, Yiwen, 1982-
(författare)
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Interplay Between Cell of Origin and Oncogenic Activation in Glioma
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glioma is the most frequent primary tumor of the central nervous system. By using the RCAS/tv-a mouse glioma model, we have studied mechanisms controlling glioma development and the effect of cell of origin on these processes.SOX5 was identified as a brain tumor locus in a retroviral insertional mutagenesis screen of PDGF-B induced mouse gliomas. Here we found that SOX5 could suppress PDGFB-induced glioma development particularly in Ink4a-/- mice. Analysis of putative PDGF-B signaling pathways revealed that the underlying mechanism could involve the activation of AKT and p27, which caused an acute cellular senescence.When cultured in a highly selective serum free medium, glioma-initiating cells could be isolated from mouse GBMs and their self-renewal and proliferation was independent on exogenous EGF and FGF2. Addition of serum into the medium induced aberrant differentiation that was reversible. Specific depletion of viral PDGF-B demonstrated that PDGF-B was necessary for stemness and tumorigenicity of GICs by preventing them to differentiate.Subsequently, by applying the same culture conditions, GICs of APC, NSC and OPC origins were isolated from mouse GBMs. GICs derived from NSCs exhibited higher self-renewal, faster proliferation and more potent tumorigenicity than those of APC or OPC origin. Furthermore, addition of 5% serum significantly inhibited the proliferation of APC- and OPC-derived GICs, but did not in NSC-derived GICs. Transcriptome analysis revealed that GICs of the same cell of origin displayed distinct expression profiles.In the last study, we showed that OPCs could serve as the origin for astrocytic glioma. Results from immunostainings revealed that these tumors might belong to a different molecular subtype than the oligodendroglial tumors induced in OPCs. We also found differences in tumorigenic potential between OPCs in neonatal and adult mice, which suggest that developmental age of the cell of origin is important for its susceptibility to oncogenic transformation.
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| 24. |
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| 25. |
- Jiang, Yiwen, et al.
(författare)
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On the origin of glioma
- 2012
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 117:2, s. 113-121
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Tidskriftsartikel (refereegranskat)abstract
- Glioma is the most frequent primary brain tumor of adults that has a presumably glial origin. Although our knowledge regarding molecular mechanisms and signaling pathways involved in gliomagenesis has increased immensely during the past decade, high-grade glioma remains a lethal disease with dismal prognosis. The failure of current therapies has to a large extent been ascribed the functional heterogeneity of glioma cells. One reason for this heterogeneity is most certainly the large number of variations in genetic alterations that can be found in high-grade gliomas. Another factor that may influence glioma heterogeneity could be the cell type from which the glioma is initiated. The cell of origin for glioma is still undefined, and additional knowledge about this issue may prove critical for a more complete understanding of glioma biology. Based on information from patients, developmental biology, and experimental glioma models, the most putative target cells include astrocytes, neural stem cells, and oligodendrocyte precursor cells, which are all discussed in more detail in this article. Animal modeling of glioma suggests that these three cell types have the capability to be the origin of glioma, and we have reason to believe that, depending on the initiating cell type, prognosis and response to therapy may be significantly different. Thus, it is essential to explore further the role of cellular origin in glioma.
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