Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition

Segerman, Anna; Niklasson, Mia; Haglund, Caroline; Bergström, Tobias; Jarvius, Malin; Xie, Yuan; Westermark, Ann; Sönmez, Demet; Hermansson, Annika; Kastemar, Marianne; Naimaie-Ali, Zeinab; Nyberg, Frida; Berglund, Malin; Sundström, Magnus; Hesselager, Göran; Uhrbom, Lene; Gustafsson, Mats; Larsson, Rolf; Fryknäs, Mårten; Segerman, Bo; Westermark, Bengt

doi:10.1016/j.celrep.2016.11.056

Cited by 177 publications

(215 citation statements)

References 35 publications

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“…S2). As has been demonstrated by others (3, 4), expression of MES and PN genes exists on a spectrum with high enrichment of the MES genes predicting low expression of the PN genes. All patients were then subtyped according to MES or PN gene signatures (41) and enrichment of translation (TLN I) and translation initiation (TLN II) gene sets was compared (Fig.…”

Section: Resultssupporting

confidence: 55%

“…When compared with PN GSCs, MES GSCs are particularly resistant to a number of different cytotoxic agents and radiation. Several mechanisms have been identified as drivers of this resistance in MES GSCs including reliance on different metabolic pathways, FOX transcription factor programs, regulatory microRNAs, and altered epigenetic states (2, 3, 39, 42). Furthermore, single-cell sequencing studies have uncovered a phenomenon in which individual GBM tumors contain clones of different molecular subtypes (i.e., intratumoral heterogeneity; ref.…”

Section: Discussionmentioning

confidence: 99%

“…MES and PN GSCs are tumor-initiating cells that can be found concurrently within the same tumors, and increased intratumoral heterogeneity promotes a more resistant phenotype (3, 4). Effective treatment of GBM will require the development of therapies that specifically target these distinct GSC populations.…”

Section: Introductionmentioning

confidence: 99%

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Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation

Bell

Eckerdt

Dhruv

et al. 2018

Molecular Cancer Research

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Mesenchymal (MES) and proneural (PN) are two distinct glioma stem cell (GSC) populations that drive therapeutic resistance in glioblastoma (GBM). We screened a panel of 650 small molecules against patient-derived GBM cells to discover compounds targeting specific GBM subtypes. Arsenic trioxide (ATO), an FDA-approved drug that crosses the blood–brain barrier, was identified as a potent PN-specific compound in the initial screen and follow-up validation studies. Furthermore, MES and PN GSCs exhibited differential sensitivity to ATO. As ATO has been shown to activate the MAPK-interacting kinase 1 (MNK1)-eukaryotic translation initiation factor 4E (eIF4E) pathway and subsequent mRNA translation in a negative regulatory feedback manner, the mechanistic role of ATO resistance in MES GBM was explored. In GBM cells, ATO-activated translation initiation cellular events via the MNK1–eIF4E signaling axis. Furthermore, resistance to ATO in intracranial PDX tumors correlated with high eIF4E phosphorylation. Polysomal fractionation and microarray analysis of GBM cells were performed to identify ATO’s effect on mRNA translation and enrichment of anti-apoptotic mRNAs in the ATO-induced translatome was found. Additionally, it was determined that MNK inhibition sensitized MES GSCs to ATO in neurosphere and apoptosis assays. Finally, examination of the effect of ATO on patients from a phase I/II clinical trial of ATO revealed that PN GBM patients responded better to ATO than other subtypes as demonstrated by longer overall and progression-free survival. Implications These findings raise the possibility of a unique therapeutic approach for GBM, involving MNK1 targeting to sensitize MES GSCs to drugs like arsenic trioxide.

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Section: Resultssupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

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Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation

Bell

Eckerdt

Dhruv

et al. 2018

Molecular Cancer Research

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“…The existence of different molecular subtypes within a tumor [30] and at single cell level [31, 32] was demonstrated using genome wide gene expression analysis. Using fluorescence-guided multiple sampling approach, Sottoriva and colleagues showed that GBM tumor fragments harvested from spatially distinct location within the tumor can be classified into different molecular subtypes based on their gene expression profile [30].…”

Section: Molecular Heterogeneity Of Gbmmentioning

confidence: 99%

“…Importantly, the group demonstrated that increased heterogeneity of the tumor correlates with poorer survival [31]. Using large-scale clonal analysis of glioma-initiating cells harvested from primary GBM, Segerman et al further revealed the widespread and extensive heterogeneity that correspond to response to radiation and chemotherapy [32]. Resistant clones were associated with the mesenchymal cell state, which is consistent with previous reports in GBM and other carcinomas in which mesenchymal phenotype is associated with increased therapeutic resistance [34–36].…”

Section: Molecular Heterogeneity Of Gbmmentioning

confidence: 99%

Contribution of the Microenvironmental Niche to Glioblastoma Heterogeneity

Shim

2017

BioMed Research International

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Glioblastoma is the most aggressive cancer of the brain. The dismal prognosis is largely attributed to the heterogeneous nature of the tumor, which in addition to intrinsic molecular and genetic changes is also influenced by the microenvironmental niche in which the glioma cells reside. The cancer stem cells (CSCs) hypothesis suggests that all cancers arise from CSCs that possess the ability to self-renew and initiate tumor formation. CSCs reside in specialized niches where interaction with the microenvironment regulates their stem cell behavior. The reciprocal interaction between glioma stem cells (GSCs) and cells from the microenvironment, such as endothelial cells, immune cells, and other parenchymal cells, may also promote angiogenesis, invasion, proliferation, and stemness of the GSCs and be likely to have an underappreciated role in their responsiveness to therapy. This crosstalk may also promote molecular transition of GSCs. Hence the inherent plasticity of GSCs can be seen as an adaptive response, changing according to the signaling cue from the niche. Given the association of GSCs with tumor recurrence and treatment sensitivity, understanding this bidirectional crosstalk between GSCs and its niche may provide a framework to identify more effective therapeutic targets and improve treatment outcome.

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Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma

et al. 2018

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TWIST1 (TW) is a bHLH transcription factor (TF) and master regulator of the epithelial‐to‐mesenchymal transition (EMT). In vitro, TW promotes mesenchymal change, invasion, and self‐renewal in glioblastoma (GBM) cells. However, the potential therapeutic relevance of TW has not been established through loss‐of‐function studies in human GBM cell xenograft models. The effects of TW loss of function (gene editing and knockdown) on inhibition of tumorigenicity of U87MG and GBM4 glioma stem cells were tested in orthotopic xenograft models and conditional knockdown in established flank xenograft tumors. RNAseq and the analysis of tumors investigated putative TW‐associated mechanisms. Multiple bioinformatic tools revealed significant alteration of ECM, membrane receptors, signaling transduction kinases, and cytoskeleton dynamics leading to identification of PI3K/AKT signaling. We experimentally show alteration of AKT activity and periostin (POSTN) expression in vivo and/or in vitro. For the first time, we show that effect of TW knockout inhibits AKT activity in U87MG cells in vivo independent of PTEN mutation. The clinical relevance of TW and candidate mechanisms was established by analysis of the TCGA and ENCODE databases. TW expression was associated with decreased patient survival and LASSO regression analysis identified POSTN as one of top targets of TW in human GBM. While we previously demonstrated the role of TW in promoting EMT and invasion of glioma cells, these studies provide direct experimental evidence supporting protumorigenic role of TW independent of invasion in vivo and the therapeutic relevance of targeting TW in human GBM. Further, the role of TW driving POSTN expression and AKT signaling suggests actionable targets, which could be leveraged to mitigate the oncogenic effects of TW in GBM.

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Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition

Cited by 177 publications

References 35 publications

Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation

Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation

Contribution of the Microenvironmental Niche to Glioblastoma Heterogeneity

Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma

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