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Jiang, Yiwen
Publications (10 of 10) Show all publications
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
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
Zhang, L., Laaniste, L., Jiang, Y., Alafuzoff, I., Uhrbom, L. & Dimberg, A. (2016). Pleiotrophin enhances PDGFB-induced gliomagenesis through increased proliferation of neural progenitor cells. OncoTarget, 7(49), 80382-80390
Open this publication in new window or tab >>Pleiotrophin enhances PDGFB-induced gliomagenesis through increased proliferation of neural progenitor cells
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 49, p. 80382-80390Article in journal (Refereed) Published
Abstract [en]

Pleiotrophin (PTN) augments tumor growth by increasing proliferation of tumor cells and promoting vascular abnormalization, but its role in early gliomagenesis has not been evaluated. Through analysis of publically available datasets, we demonstrate that increased PTN mRNA expression is associated with amplification of chromosome 7, identified as one of the earliest steps in glioblastoma development. To elucidate the role of PTN in tumor initiation we employed the RCAS/tv-a model that allows glioma induction by RCAS-virus mediated expression of oncogenes in neural progenitor cells. Intracranial injection of RCAS-PTN did not induce glioma formation when administrated alone, but significantly enhanced RCAS-platelet derived growth factor (PDGF) B-induced gliomagenesis. PTN co-treatment augmented PDGFBinduced Akt activation in neural progenitor cells in vitro, and enhanced neural sphere size associated with increased proliferation. Our data indicates that PTN expression is associated with chromosome 7 gain, and that PTN enhances PDGFB-induced gliomagenesis by stimulating proliferation of neural progenitor cells.

Keywords
glioma, pleiotrophin, gliomagenesis, tumor initiation, chromosome 7
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-313533 (URN)10.18632/oncotarget.12983 (DOI)000389877500027 ()
Funder
Swedish Cancer Society, CAN 2011/862 CAN 2014/832 CAN 2015/1216Swedish Childhood Cancer Foundation, PR2013-0107 PR2015-0133 NCp2015-0075Swedish Research Council, 2013-3797
Available from: 2017-02-02 Created: 2017-01-20 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, 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) Clinical Laboratory Medicine
Research subject
Pathology; Pathology
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: 2019-04-02Bibliographically 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
Savary, K., Caglayan, D., Caja, L., Tzavlaki, K., Bin Nayeem, S., Bergström, T., . . . Moustakas, A. (2013). Snail depletes the tumorigenic potential of glioblastoma. Oncogene, 32(47), 5409-5420
Open this publication in new window or tab >>Snail depletes the tumorigenic potential of glioblastoma
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2013 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 47, p. 5409-5420Article in journal (Refereed) Published
Abstract [en]

Glioblastoma multiforme (GBM) is an aggressive brain malignancy characterized by high heterogeneity and invasiveness. It is increasingly accepted that the refractory feature of GBM to current therapies stems from the existence of few tumorigenic cells that sustain tumor growth and spreading, the so-called glioma-initiating cells (GICs). Previous studies showed that cytokines of the bone morphogenetic protein (BMP) family induce differentiation of the GICs, and thus act as tumor suppressors. Molecular pathways that explain this behavior of BMP cytokines remain largely elusive. Here, we show that BMP signaling induces Smad-dependent expression of the transcriptional regulator Snail in a rapid and sustained manner. Consistent with its already established promigratory function in other cell types, we report that Snail silencing decreases GBM cell migration. Consequently, overexpression of Snail increases GBM invasiveness in a mouse xenograft model. Surprisingly, we found that Snail depletes the GBM capacity to form gliomaspheres in vitro and to grow tumors in vivo, both of which are important features shared by GICs. Thus Snail, acting downstream of BMP signaling, dissociates the invasive capacity of GBM cells from their tumorigenic potential.

Keywords
BMP, glioblastoma multiforme, glioma initiating cells, invasiveness, Snail
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-182944 (URN)10.1038/onc.2013.67 (DOI)000327177600004 ()23524585 (PubMedID)
Available from: 2012-10-19 Created: 2012-10-19 Last updated: 2018-12-03Bibliographically approved
Põlajeva, J., Swartling, F., Jiang, Y., Singh, U., Pietras, K., Uhrbom, L., . . . Roswall, P. (2012). miRNA-21 is developmentally regulated in mouse brain and is co-expressed with SOX2 in glioma. BMC Cancer, 12, 378
Open this publication in new window or tab >>miRNA-21 is developmentally regulated in mouse brain and is co-expressed with SOX2 in glioma
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2012 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, p. 378-Article in journal (Refereed) Published
Abstract [en]

Background

MicroRNAs (miRNAs) and their role during tumor development have been studied in greatdetail during the last decade, albeit their expression pattern and regulation during normaldevelopment are however not so well established. Previous studies have shown that miRNAsare differentially expressed in solid human tumors. Platelet-derived growth factor (PDGF)signaling is known to be involved in normal development of the brain as well as in malignantprimary brain tumors, gliomas, but the complete mechanism is still lacking. We decided toinvestigate the expression of the oncogenic miR-21 during normal mouse development andglioma, focusing on PDGF signaling as a potential regulator of miR-21.

Methods

We generated mouse glioma using the RCAS/tv-a system for driving PDGF-BB expression ina cell-specific manner. Expression of miR-21 in mouse cell cultures and mouse brain wereassessed using Northern blot analysis and in situ hybridization. Immunohistochemistry andWestern blot analysis were used to investigate SOX2 expression. LNA-modified siRNA wasused for irreversible depletion of miR-21. For inhibition of PDGF signaling Gleevec(imatinib mesylate), Rapamycin and U0126, as well as siRNA were used. Statisticalsignificance was calculated using double-sided unpaired Student´s t-test.

Results

We identified miR-21 to be highly expressed during embryonic and newborn braindevelopment followed by a gradual decrease until undetectable at postnatal day 7 (P7), thiscorrelated with SOX2 expression. Furthermore, miR-21 and SOX2 showed up-regulation andoverlapping expression pattern in RCAS/tv-a generated mouse brain tumor specimens. Uponirreversible depletion of miR-21 the expression of SOX2 was strongly diminished in bothmouse primary glioma cultures and human glioma cell lines. Interestingly, in normalfibroblasts the expression of miR-21 was induced by PDGF-BB, and inhibition of PDGFsignaling in mouse glioma primary cultures resulted in suppression of miR-21 suggesting thatmiR-21 is indeed regulated by PDGF signaling.

Conclusions

Our data show that miR-21 and SOX2 are tightly regulated already during embryogenesisand define a distinct population with putative tumor cell of origin characteristics. We believethat miR-21 is a mediator of PDGF-driven brain tumors, which suggests miR-21 as apromising target for treatment of glioma.

Keywords
miRNA, miR-21, Glioma, PDGF-BB, SOX2, Imatinib (Gleevec), RCAS/tv-a
National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:uu:diva-180243 (URN)10.1186/1471-2407-12-378 (DOI)000312098700001 ()
Available from: 2012-09-01 Created: 2012-09-01 Last updated: 2017-12-07Bibliographically approved
Jiang, Y. & Uhrbom, L. (2012). On the origin of glioma. Upsala Journal of Medical Sciences, 117(2), 113-121
Open this publication in new window or tab >>On the origin of glioma
2012 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 117, no 2, p. 113-121Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Astrocyte, cell of origin, glioma, glioma-initiating cell, neural stem cell, oligodendrocyte precursor cell
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-174364 (URN)10.3109/03009734.2012.658976 (DOI)000302949200005 ()
Available from: 2012-05-24 Created: 2012-05-15 Last updated: 2017-12-07Bibliographically approved
Tchougounova, E., Jiang, Y., Bråsäter, D., Lindberg, N., Kastemar, M., Asplund, A., . . . Uhrbom, L. (2009). Sox5 can suppress platelet-derived growth factor B-induced glioma development in Ink4a-deficient mice through induction of acute cellular senescence. Oncogene, 28(12), 1537-1548
Open this publication in new window or tab >>Sox5 can suppress platelet-derived growth factor B-induced glioma development in Ink4a-deficient mice through induction of acute cellular senescence
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2009 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 28, no 12, p. 1537-1548Article in journal (Refereed) Published
Abstract [en]

SOX5 is a member of the high-mobility group superfamily of architectural non-histone proteins involved in gene regulation and maintenance of chromatin structure in a wide variety of developmental processes. Sox5 was identified as a brain tumor locus in a retroviral insertional mutagenesis screen of platelet-derived growth factor B (PDGFB)-induced mouse gliomas. Here we have investigated the role of Sox5 in PDGFB-induced gliomagenesis in mice. We show that Sox5 can suppress PDGFB-induced glioma development predominantly upon Ink4a-loss. In human glioma cell lines and tissues, we found very low levels of SOX5 compared with normal brain. Overexpression of Sox5 in human glioma cells led to a reduction in clone formation and inhibition of proliferation. Combined expression of Sox5 and PDGFB in primary brain cell cultures caused decreased proliferation and an increased number of senescent cells in the Ink4a-/- cells only. Protein analyses showed a reduction in the amount and activation of Akt and increased levels of p27(Kip1) upon Sox5 expression that was dominant to PDGFB signaling and specific to Ink4a-/- cells. Upon inhibition of p27(Kip1), the effects of Sox5 on proliferation and senescence could be reversed. Our data suggest a novel pathway, where Sox5 may suppress the oncogenic effects of PDGFB signaling during glioma development by regulating p27(Kip1) in a p19(Arf)-dependent manner, leading to acute cellular senescence.

Keywords
Sox5, glioma, PDGF, p27(Kip1), senescence
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-102252 (URN)10.1038/onc.2009.9 (DOI)000264537400006 ()19219070 (PubMedID)
Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2017-12-13Bibliographically approved
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