Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin

Jiang, Yiwen; Marinescu, Voichita D.; Xie, Yuan; Jarvius, Malin; Maturi, Naga Prathyusha; Haglund, Caroline; Olofsson, Sara K.; Lindberg, Nanna; Olofsson, Tommie; Leijonmarck, Caroline; Hesselager, Göran; Alafuzoff, Irina; Fryknäs, Mårten; Larsson, Rolf; Nelander, Sven; Uhrbom, Lene

doi:10.1016/j.celrep.2017.04.053

Cited by 21 publications

(47 citation statements)

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“…LGR5 gene expression was analyzed in 60 patient-derived GSC cultures [8] that had been reclassified [7]; ordered based on LGR5 expression; and divided by quartiles into LGR5 low , LGR5 intermediate , and…”

Section: Resultsmentioning

confidence: 99%

“…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.No conflicts of interest were declared. tumors were initially distributed over four subtypes: proneural, classical, mesenchymal, and neural [5,6], but in the latest classification, the neural subtype was omitted [7].We recently demonstrated that the cell of origin could influence the phenotype of GBM cells [8], where a stem cell-like origin produced GSCs that were more malignant and more sensitive to drugs than a more differentiated precursor cell origin. Furthermore, we identified a mouse cell origin (MCO) gene signature that could be used to stratify patient-derived GSCs into functionally distinct groups.LGR5 was part of that signature and a marker of stem cell origin.Cells were transfected with siNT (a mixture of four individual nontarget siRNAs) or siLGR5 (a mixture of four individual siRNAs targeting LGR5) as described in supplementary material, Supplementary materials and methods.The role of LGR5 on cell motility was further examined in vitro.…”

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confidence: 99%

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LGR5 promotes tumorigenicity and invasion of glioblastoma stem‐like cells and is a potential therapeutic target for a subset of glioblastoma patients

Xie

Sundström

Maturi

et al. 2019

The Journal of Pathology

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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 (LGR5high), 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 LGR5high‐ELDAhigh cultures were also significantly more malignant and invasive compared to the LGR5high‐ELDAlow 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 © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

LGR5 promotes tumorigenicity and invasion of glioblastoma stem‐like cells and is a potential therapeutic target for a subset of glioblastoma patients

Xie

Sundström

Maturi

et al. 2019

The Journal of Pathology

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“…Similarly, increased growth of A172-GFP/luc was detected in co-culture formats with fivefold higher number of HA (Figure 2d). In order to consolidate these cell line-derived findings, the effect of astrocytes was analyzed on the U3013-GFP/luc GBM patientderived culture (Jiang et al, 2017). In a 96-well plate, 500 U3013-GFP/luc cells were seeded with or without 1,000 HA.…”

Section: Astrocytes Stimulate the Growth Of Established Gbm Cell LImentioning

confidence: 99%

Astrocytes enhance glioblastoma growth

Mega

Nilsen

Leiss

et al. 2019

Glia

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Glioblastoma (GBM) is a deadly disease with a need for deeper understanding and new therapeutic approaches. The microenvironment of glioblastoma has previously been shown to guide glioblastoma progression. In this study, astrocytes were investigated with regard to their effect on glioblastoma proliferation through correlative analyses of clinical samples and experimental in vitro and in vivo studies. Co‐culture techniques were used to investigate the GBM growth enhancing potential of astrocytes. Cell sorting and RNA sequencing were used to generate a GBM‐associated astrocyte signature and to investigate astrocyte‐induced GBM genes. A NOD scid GBM mouse model was used for in vivo studies. A gene signature reflecting GBM‐activated astrocytes was associated with poor prognosis in the TCGA GBM dataset. Two genes, periostin and serglycin, induced in GBM cells upon exposure to astrocytes were expressed at higher levels in cases with high “astrocyte signature score”. Astrocytes were shown to enhance glioblastoma cell growth in cell lines and in a patient‐derived culture, in a manner dependent on cell–cell contact and involving increased cell proliferation. Furthermore, co‐injection of astrocytes with glioblastoma cells reduced survival in an orthotopic GBM model in NOD scid mice. In conclusion, this study suggests that astrocytes contribute to glioblastoma growth and implies this crosstalk as a candidate target for novel therapies.

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“…In vivo orthotopic implantations of xenograft-derived cells revealed that high integrin α7-cells are more proliferative and invasive, suggesting that these undifferentiated GSCs constitute a group of highly aggressive cancer cells. This hypothesis is supported by Jiang et al [2017] studies, where the authors demonstrated that glioma malignancy is dependent on the cell of origin (12). Jiang et al [2017] showed that undifferentiated cellderived tumors become more invasive and aggressive when compared to more differentiated, nestin-and glial fibrillary acidic protein (GFAP)-positive cellderived tumors.…”

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confidence: 95%

“…These opposing results may be explained by differences in the cells driving each type of cancer. Recent reports show that stem cell derived-gliomas display higher malignancy when compared to differentiating-cell derived tumors (12,21). Other studies show that prostate cancer growth can be mediated by luminal or basal differentiatingcells as reviewed in (22), while melanomas can be derived from both stem cell precursors or differentiating melanocytes depending on microenvironment (23,24).…”

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confidence: 99%