scholarly journals Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3

2016 ◽  
Author(s):  
Maureen M. Sherry-Lynes ◽  
Sejuti Sengupta ◽  
Shreya Kulkarni ◽  
Brent H. Cochran
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Types ◽  
Self Renewal ◽  
Glioblastoma Stem Cells ◽  
Glioblastoma Stem Cell ◽  
Histone H3k27 ◽  
Direct Target ◽  
Polycomb Complex ◽  
Stat3 Inhibition

SUMMARYThe growth factor and cytokine regulated transcription factor STAT3 is required for the self-renewal of several stem cell types including tumor stem cells from glioblastoma. Here we show that STAT3 inhibition leads to the upregulation of the histone H3K27me2/3 demethylase Jmjd3 (KDM6B), which can reverse polycomb complex-mediated repression of tissue specific genes. STAT3 binds to the Jmjd3 promoter, suggesting that Jmjd3 is a direct target of STAT3. Overexpression of Jmjd3 slows glioblastoma stem cell growth and neurosphere formation, whereas knockdown of Jmjd3 rescues the STAT3 inhibitor-induced neurosphere formation defect. Consistent with this observation, STAT3 inhibition leads to histone H3K27 demethylation of neural differentiation genes, such as Myt1, FGF21, and GDF15. These results demonstrate that the regulation of Jmjd3 by STAT3 maintains repression of differentiation specific genes and is therefore important for the maintenance of self-renewal of normal neural and glioblastoma stem cells.

scholarly journals DYRK1A Negatively Regulates CDK5-SOX2 Pathway and Self-Renewal of Glioblastoma Stem Cells

2021 ◽  
Vol 22 (8) ◽  
pp. 4011
Author(s):  
Brianna Chen ◽  
Dylan McCuaig-Walton ◽  
Sean Tan ◽  
Andrew P. Montgomery ◽  
Bryan W. Day ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Critical Role ◽  
Stem Cell Differentiation ◽  
Neural Progenitor Cell ◽  
Cellular Heterogeneity ◽  
Differentiation Potential ◽  
Glioblastoma Stem Cells ◽  
Glioblastoma Stem Cell

Glioblastoma display vast cellular heterogeneity, with glioblastoma stem cells (GSCs) at the apex. The critical role of GSCs in tumour growth and resistance to therapy highlights the need to delineate mechanisms that control stemness and differentiation potential of GSC. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) regulates neural progenitor cell differentiation, but its role in cancer stem cell differentiation is largely unknown. Herein, we demonstrate that DYRK1A kinase is crucial for the differentiation commitment of glioblastoma stem cells. DYRK1A inhibition insulates the self-renewing population of GSCs from potent differentiation-inducing signals. Mechanistically, we show that DYRK1A promotes differentiation and limits stemness acquisition via deactivation of CDK5, an unconventional kinase recently described as an oncogene. DYRK1A-dependent inactivation of CDK5 results in decreased expression of the stemness gene SOX2 and promotes the commitment of GSC to differentiate. Our investigations of the novel DYRK1A-CDK5-SOX2 pathway provide further insights into the mechanisms underlying glioblastoma stem cell maintenance.

scholarly journals Circular RNAs in Stem Cells: from Basic Research to Clinical Implications

2021 ◽  
Author(s):  
Hui-Juan Lu ◽  
Juan Li ◽  
Guodong Yang ◽  
Cun-Jian Yi ◽  
Daping Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Biology ◽  
Basic Research ◽  
Cell Types ◽  
Circular Rnas ◽  
Diagnostic Significance ◽  
Differentiation Potential ◽  
Self Renewal ◽  
Cell Based Therapy

Circular RNAs (circRNAs) are a special class of endogenous RNAs with a wide variety of pathophysiological functions via diverse mechanisms, including transcription, miRNA sponge, protein sponge/decoy, and translation. Stem cells are pluripotent cells with unique properties of self-renewal and differentiation. Dysregulated circRNAs identified in various stem cell types can affect stem cell self-renewal and differentiation potential by manipulating stemness. However, the emerging roles of circRNAs in stem cells remain largely unknown. This review summarizes the major functions and mechanisms of action of circRNAs in stem cell biology and disease progression. We also highlight circRNAs-mediated common pathways in diverse stem cell types and discuss their diagnostic significance with respect to stem cell-based therapy.

Evaluation of the Role of STAT3 in the Self-Renewal of Primitive Chronic Myelogenous Leukemia (CML) Stem Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1076-1076
Author(s):  
Severine Marti N-Lannerée ◽  
Marie-Laure Bonnet ◽  
Caroline Mayeur-Rousse ◽  
Angelina Bertrand ◽  
Marie-Claude Meunier ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Chronic Myelogenous Leukemia ◽  
The Self ◽  
Myelogenous Leukemia ◽  
Cell Level ◽  
Self Renewal ◽  
Cd34 Cells ◽  
Stat3 Inhibition

Abstract In previous experiments we have demonstrated that BCR-ABL activates specifically STAT3 in the context of murine ES cells and in leukemic CD34+ cells in patients with chronic myelogenous leukemia. This activation occurs essentially through Tyr705 and Ser 727 phosphorylation and implicates Jak2 and MEK pathways (Coppo et al, Brit J Haematol, 2006). However, it is not known if STAT3 activation plays a role in the self-renewal of primitive stem cells or if it is predominantly involved in BCR-ABL-associated leukemogenesis. To determine the role of STAT3 at the primitive stem cell level, we have inhibited specifically STAT3 expression by using a shRNA-GFP-STAT3 construct which was lentivirally transduced into purified CD34+ cells from patients with CML. Western blot experiments determined the specificity of the shRNA-STAT3 construct in hematopoietic cell lines with specific inhibition of STAT3 with no interference with STAT1, STAT5a or STAT5b expression. 8 patients with CML at diagnosis were included in the study. CD34+ cells purified from cord blood (CB) or peripheral blood stem cell (PBCS) collects were used as controls. Each sample has been transduced with high titer lentiviruses expressing either sh-STAT3 or sh-luciferase control. After transduction, GFP+ cells were purified by cell-sorting and assayed in clonogenic assays as well as in longterm- culture assays in the presence of MS-5 stromal layers with weekly half-medium changes. At week+5, clonogenic assays were performed to evaluate the numbers of LTC-IC- derived progeny. The inhibition of STAT3 expression did not alter significantly the clonogenic cell potentials in CB-CD34+ cells (n=2) or PBSC (n=1) samples. In LTC-IC assays, STAT3 inhibition resulted in 1.8-fold reduced clonogenic output in one CB-CD34+ sample and increased the same clonogenic output by 6.7-fold in the second CB sample, with no effect in LTC-IC output in CD34+ cells purified from PBSC. Amongst CML samples, the numbers of LTC-IC-derived progenitors were reduced 3-fold after shRNA-mediated STAT3 inhibition in one patient (UPN2). In all other 7 patients, inhibition of STAT3 by shRNA led to either stable ( n = 1, UPN 4) or increased ( n= 6 ) LTC-IC derived clonogenic activity, with major increase of 5-week clonogenic output in 3 patients (luciferase vs shSTAT3 clonogenic outputs 28 vs 353 for UPN5; 130 vs 270 for UPN6; 295 vs 806 for UPN8). Thus, our results suggest that STAT3 activation seen in primary CML leukemic cells does not play a role in stem cell self-renewal detectable by LTC-IC assays. On the contrary, STAT3 inhibition seems to lead to a stimulating effect of primitive stem cells in the majority of the patients analyzed. These findings do not rule out the potential role of STAT3 in BCR-ABL induced leukemogenesis but suggest that STAT3 inhibition is not a clinically useful target at the stem cell level in CML.

scholarly journals Glioblastoma Stem Cells as a New Therapeutic Target for Glioblastoma

2015 ◽  
Vol 9 ◽  
pp. CMO.S30271 ◽  
Author(s):  
Rasime Kalkan
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Signaling Pathways ◽  
Therapeutic Target ◽  
Fatal Outcome ◽  
Cellular Heterogeneity ◽  
Cell Phenotype ◽  
Glioblastoma Stem Cells ◽  
Glioblastoma Stem Cell

Primary and secondary glioblastomas (GBMs) are two distinct diseases. The genetic and epigenetic background of these tumors is highly variable. The treatment procedure for these tumors is often unsuccessful because of the cellular heterogeneity and intrinsic ability of the tumor cells to invade healthy tissues. The fatal outcome of these tumors promotes researchers to find out new markers associated with the prognosis and treatment planning. In this communication, the role of glioblastoma stem cells in tumor progression and the malignant behavior of GBMs are summarized with attention to the signaling pathways and molecular regulators that are involved in maintaining the glioblastoma stem cell phenotype. A better understanding of these stem cell-like cells is necessary for designing new effective treatments and developing novel molecular strategies to target glioblastoma stem cells. We discuss hypoxia as a new therapeutic target for GBM. We focus on the inhibition of signaling pathways, which are associated with the hypoxia-mediated maintenance of glioblastoma stem cells, and the knockdown of hypoxia-inducible factors, which could be identified as attractive molecular target approaches for GBM therapeutics.

scholarly journals Localization patterns of cathepsins K and X and their predictive value in glioblastoma

2018 ◽  
Vol 52 (4) ◽  
pp. 433-442 ◽  
Author(s):  
Barbara Breznik ◽  
Clara Limback ◽  
Andrej Porcnik ◽  
Andrej Blejec ◽  
Miha Koprivnikar Krajnc ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Stem Cell ◽  
Mrna Expression ◽  
Predictive Value ◽  
Cathepsin K ◽  
Mrna Levels ◽  
Glioblastoma Stem Cells ◽  
Glioblastoma Stem Cell ◽  
Cathepsin X

AbstractBackgroundGlioblastoma is a highly aggressive central nervous system neoplasm characterized by extensive infiltration of malignant cells into brain parenchyma, thus preventing complete tumor eradication. Cysteine cathepsins B, S, L and K are involved in cancer progression and are overexpressed in glioblastoma. We report here for the first time that cathepsin X mRNA and protein are also abundantly present in malignant glioma.Materials and methodsGene expression of cathepsins K and X was analyzed using publically-available tran-scriptomic datasets and correlated with glioma grade and glioblastoma subtype. Kaplan-Maier survival analysis was performed to evaluate the predictive value of cathepsin K and X mRNA expression. Cathepsin protein expression was localized and semi-quantified in tumor tissues by immunohistochemistry.ResultsHighest gene expression of cathepsins K and X was found in glioblastoma, in particular in the mesenchymal subtype. Overall, high mRNA expression of cathepsin X, but not that of cathepsin K, correlated with poor patients’ survival. Cathepsin K and X proteins were abundantly and heterogeneously expressed in glioblastoma tissue. Immuno-labeling of cathepsins K and X was observed in areas of CD133-positive glioblastoma stem cells, localized around arterioles in their niches that also expressed SDF-1α and CD68. mRNA levels of both cathepsins K and X correlated with mRNA levels of markers of glioblastoma stem cells and their niches.ConclusionsThe presence of both cathepsins in glioblastoma stem cell niche regions indicates their possible role in regulation of glioblastoma stem cell homing in their niches. The clinical relevance of this data needs to be elaborated in further prospective studies.

scholarly journals Dihydropyrimidinase‑related protein 5 controls glioblastoma stem cell characteristics as a biomarker of proneural‑subtype glioblastoma stem cells

2020 ◽  
Vol 20 (2) ◽  
pp. 1153-1162
Author(s):  
Min Gi Park ◽  
Sunyoung Seo ◽  
Seok Won Ham ◽  
Sang‑Hun Choi ◽  
Hyunggee Kim
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Related Protein ◽  
Glioblastoma Stem Cells ◽  
Glioblastoma Stem Cell

Origin of the Myeloma Stem Cell

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-4-SCI-4
Author(s):  
William Matsui
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
B Cells ◽  
Research Funding ◽  
Plasma Cells ◽  
Cell Types ◽  
Tumor Stem Cell ◽  
Immunoglobulin Gene ◽  
Self Renewal

Abstract Abstract SCI-4 Increasing evidence suggest that most human cancers consist of phenotypically and functionally heterogeneous cell types. Moreover, in some tumors, phenotypic-functional relationships exist and the capacity for clonogenic growth and self-renewal may be restricted to specific cell types. In multiple myeloma, malignant plasma cells make up the vast majority of tumor cells, phenotypically characterize the disease, and are responsible for clinical symptoms. However, myeloma plasma cells also appear terminally differentiated similar to their normal counterparts and incapable of long-term proliferation. Similar to other laboratories, we have identified minor populations of B cells that share the identical immunoglobulin gene rearrangements as the malignant plasma cells in most myeloma patients. We have further studied the functional capacity of these clonotypic B cells and found that they have ability to produce ectopic tumor growth both in vitro and in immunodeficient mice that can recapitulate human disease.1,2 Moreover, these cells are relatively resistant to several agents currently used to treat multiple myeloma suggesting that they have the capacity to persist following treatment and are responsible for tumor regrowth and disease relapse. In order to inhibit these drug resistant cancer stem cells, we have studied cellular pathways that regulate the self-renewal of normal adult stem cells and found that several, including the developmental pathway Hedgehog, are potential therapeutic targets.3 Finally, as these concepts are translated to the clinic, several challenges have emerged including the ability to detect activity against myeloma stem cells that make up only a minority of the overall tumor burden.4 To this end, we have begun to develop biomarker strategies to serially quantify myeloma stem cells in patients undergoing treatment and will examine their utility as clinical endpoints. 1. Matsui W, Huff CA, Wang Q, et al. Characterization of clonogenic multiple myeloma cells. Blood. 2004;103:2332–2336. 2. Matsui W, Wang Q, Barber JP, et al. Clonogenic Multiple Myeloma Progenitors, Stem Cell Properties, and Drug Resistance. Cancer Research. 2008;68:190–197. 3. Peacock CD, Wang Q, Gesell GS, et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proceedings of the National Academy of Sciences, USA. 2007;104:4048–4053. 4. Huff CA, Matsui W, Smith BD, Jones RJ. The paradox of response and survival in cancer therapeutics. Blood. 2006;107:431–434. Disclosures: Matsui: Pfizer: Consultancy; Bristol-Meyers Squibb: Consultancy; Infinity Phamaceuticals: Consultancy, Patents & Royalties; Merck: Consultancy, Research Funding; Geron Corporation: Research Funding. Off Label Use: Rituximab in multiple myeloma.

scholarly journals TMIC-22. IDENTIFICATION OF CANCER-ASSOCIATED FIBROBLASTS IN GLIOBLASTOMA and Defining Their Protumoral Effects

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi252-vi252
Author(s):  
Jonathan Rick ◽  
Alan Nguyen ◽  
Ankush Chandra ◽  
Harsh Wadhwa ◽  
Sumedh Shah ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Cancer Associated Fibroblasts ◽  
Rna Seq ◽  
Glioblastoma Stem Cells ◽  
Perivascular Niche ◽  
Glioblastoma Stem Cell ◽  
Blocking Antibodies

Abstract While cancer-associated fibroblasts (CAFs) and their pro-tumoral effects have been demonstrated in systemic cancers, CAFs had been presumed absent in glioblastoma given the lack of normal fibroblasts in the healthy brain. Here, we show that 5–26% (mean=12%) of cells in human glioblastomas express CAF markers α-SMA or PDGFR-β, morphologically resemble fibroblasts, and transcriptomically resemble by RNA-seq CAFs from other cancers. Glioblastoma CAFs were chemotactically attracted to glioblastoma-initiating stem cells (P=0.02). While glioblastoma CAFs did not affect differentiated glioblastoma cell proliferation (P=0.4), CAFs increased glioblastoma stem cell proliferation (P=0.002) and expression of glioblastoma stem cell-associated genes (P< 0.001). To identify mediators of CAF/glioblastoma stem cell interactions, we created a resource of inferred crosstalk by mapping the expression of receptors to that of their cognate ligands/agonists, using our RNA-seq results from glioblastoma CAFs and stem cells, revealing PDGF-β/PDGFR and osteopontin/CD44 to mediate stem cell recruitment of CAFs and CAF enrichment of stem cells, as confirmed by blocking antibodies (P=0.02–0.03). CAFs also render the glioblastoma microenvironment more pro-tumoral by promoting M2 polarization of tumor-associated macrophages (P=0.01), an effect we found to arise from unique CAF production of the EDA splice variant of fibronectin binding toll-like receptor 4 (TLR4), a known EDA receptor expressed by macrophages (P=0.02). In patient glioblastomas, CAFs were enriched 3-fold in the subventricular zone (SVZ) (P=0.04) which houses the neural stem cells that generate glioblastoma stem cells. SVZs from epilepsy cases or autopsies of glioblastoma-containing brains without ventricular involvement lacked CAFs. Depleting CAFs in xenografts derived from neurosphere-containing glioblastoma stem cells slowed their growth in vivo (P< 0.001). These findings are among the first to identify and profile glioblastoma CAFs. CAF recruitment by glioblastoma stem cells and creation of a pro-tumoral microenvironment in the perivascular niche housing glioblastoma stem cells, particularly in the SVZ, makes them an intriguing therapeutic target.

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