ZEB1 regulates glioma stemness through LIF repression

Edwards, Lincoln; Li, Aiguo; Berel, Dror; Madany, Mecca; Kim, Nam-Ho; Liu, Minzhi; Hymowitz, Mitch; Uy, Benjamin R.; Jung, Rachel S.; Xu, Minlin; Black, Keith L.; Rentsendorj, Altan; Fan, Xuemo; Zhang, Wei; Yu, John S.

doi:10.1038/s41598-017-00106-x

Cited by 30 publications

(21 citation statements)

References 42 publications

(52 reference statements)

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“…Therefore, we inferred that it was more likely a regulation rather than selection. The stemness induced by EMT was reported to be regulated in conventional cell lines by various genes, such as ZEB1, Twist1, Slug, Snail, and Vimentin [5,74,85]. We saw a similar pattern where the EMT was regulated by different factors in the individual lines, but we observed a temporarily upregulated self-renewal capacity under chemotherapeutic stress in primary BCSCs (Figure 5).…”

Section: Discussionsupporting

confidence: 54%

Chemotherapeutic Stress Influences Epithelial–Mesenchymal Transition and Stemness in Cancer Stem Cells of Triple-Negative Breast Cancer

Xiao

Strietz

Bleilevens

et al. 2020

IJMS

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Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen and progesterone receptors (ER, PR) and lacking an overexpression of human epidermal growth factor receptor 2 (HER2). Apart from this lack of therapeutic targets, TNBC also shows an increased capacity for early metastasis and therapy resistance. Currently, many TNBC patients receive neoadjuvant chemotherapy (NACT) upon detection of the disease. With TNBC likely being driven at least in part by a cancer stem-like cell type, we wanted to evaluate the response of primary cancer stem cells (CSCs) to standard chemotherapeutics. Therefore, we set up a survival model using primary CSCs to mimic tumor cells in patients under chemotherapy. Breast cancer stem cells (BCSCs) were exposed to chemotherapeutics with a sublethal dose for six days. Surviving cells were allowed to recover in culture medium without chemotherapeutics. Surviving and recovered cells were examined in regard to proliferation, migratory capacity, sphere forming capacity, epithelial–mesenchymal transition (EMT) factor expression at the mRNA level, and cancer-related microRNA (miRNA) profile. Our results indicate that chemotherapeutic stress enhanced sphere forming capacity of BCSCs, and changed cell morphology and EMT-related gene expression at the mRNA level, whereas the migratory capacity was unaffected. Six miRNAs were identified as potential regulators in this process.

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Section: Discussionsupporting

confidence: 54%

Chemotherapeutic Stress Influences Epithelial–Mesenchymal Transition and Stemness in Cancer Stem Cells of Triple-Negative Breast Cancer

Xiao

Strietz

Bleilevens

et al. 2020

IJMS

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“…Additional IDH1 wt super-enhancers marked by 5hmC in our dataset and implicated in GBM pathogenesis included WDR1 , TGFBI and PVT1 [ 11 , 36 , 43 , 74 ]. IDH1 mt-specific super-enhancer targets marked by 5hmC in our cohort and previously implicated in GBM pathogenesis included PDGFC , PRRX1 , LIF , A XL , and CD44 [ 14 , 18 , 31 , 50 , 55 , 63 , 71 ]. Taken together, these data demonstrated enhancer/super-enhancer targeting by 5hmC as a prominent feature in HGG, with differential targeting observed between IDH1 cohorts.…”

Section: Discussionmentioning

confidence: 91%

5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma

et al. 2018

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Gliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role in IDH1 mutant gliomas is incompletely understood. To characterize 5hmC in IDH1 mutant gliomas further, we examine 5hmC in a cohort of IDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Regions demonstrating high 5hmC abundance and differentially hydroxymethylated regions (DHMR) enrich for enhancers implicated in glioma pathogenesis. Among these regions, IDH1 mutant tumors possess greater 5hmC compared to wild type. 5hmC contributes to overall methylation status of G-CIMP genes. 5hmC targeting gene body regions correlates significantly with increased gene expression. In particular, a strong correlation between increased 5hmC and increased gene expression is identified for genes highly expressed in the IDH1 mutant cohort. Overall, locus-specific gain of 5hmC targeting regulatory regions and associated with overexpressed genes suggests a significant role for 5hmC in IDH1 mutant HGG.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1821-3) contains supplementary material, which is available to authorized users.

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“…7b-f), reflecting less differentiated, more proliferative stem cells with greater resistance to hypoxia (18). To investigate potential mediators of the increased stem-cell like behavior and mesenchymal change identified in U87-Bev R xenografts and BRGs, qPCR was performed on explanted U87-Bev R and U87-Bev S tumors for GLUT3 and ZEB1, genes associated with both properties (19,20), revealing increased GLUT3 and ZEB1 gene expression in U87-Bev R xenografts (P=1X10 -5 -0.02; Fig. 7g).…”

Section: Resultsmentioning

confidence: 99%

A novel xenograft model reveals invasive mesenchymal transition and ineffective angiogenic response during anti-angiogenic therapy resistance

Jahangiri

Chen

Chandra

et al. 2018

Preprint

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Bevacizumab treatment of glioblastoma is limited by transient responses and acquired resistance. Because of the lengthy duration of treatment that can precede resistance in patients, in order to study changes underlying the evolution of bevacizumab resistance, we created a novel multigenerational xenograft model of acquired bevacizumab resistance. Glioblastoma xenografts were treated with bevacizumab or IgG, and the fastest growing tumor reimplanted into new mice, generating paired isogeneic responsive or resistant multigenerational xenografts. Microarray analysis revealed significant overexpression across generations of the mesenchymal subtype gene signature, paralleling results from patient bevacizumab-resistant gliobalstomas (BRGs) that exhibited increasing mesenchymal gene expression correlating with increased bevacizumab treatment duration. Key mesenchymal markers, including YKL-40, CD44, SERPINE1, and TIMP1 were upregulated across generations, with altered morphology, increased invasiveness, and increased neurosphere formation confirmed in later xenograft generations. Interestingly, YKL-40 levels were elevated in serum of patients with bevacizumab-resistant vs. bevacizumab-naïve glioblastomas (52.4 vs. 24.2 ng/mL; P<0.05). Finally, despite upregulation of VEGF-independent pro-angiogenic genes across xenograft generations, immunostaining revealed increased hypoxia and decreased vessel density with increasing generation of treatment, mirroring our findings in patient BRGs and suggesting tumor growth despite effective devascularization caused by VEGF blockade. Besides identifying novel targets for preventing the evolution of resistance and offering a xenograft model for testing resistance inhibitors, our work suggests YKL-40 as a blood biomarker of bevacizumab resistance worthy of further evaluation.

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ZEB1 regulates glioma stemness through LIF repression

Cited by 30 publications

References 42 publications

Chemotherapeutic Stress Influences Epithelial–Mesenchymal Transition and Stemness in Cancer Stem Cells of Triple-Negative Breast Cancer

Chemotherapeutic Stress Influences Epithelial–Mesenchymal Transition and Stemness in Cancer Stem Cells of Triple-Negative Breast Cancer

5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma

A novel xenograft model reveals invasive mesenchymal transition and ineffective angiogenic response during anti-angiogenic therapy resistance

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