Asymmetry-Defective Oligodendrocyte Progenitors Are Glioma Precursors

Sugiarto, Sista; Persson, Anders I.; González-Muñoz, Elena; Waldhuber, Markus; Lamagna, Chrystelle; Andor, Noemi; Hanecker, Patrizia; Ayers-Ringler, Jennifer; Phillips, Joanna J.; Siu, Jason J.; Lim, Daniel A.; VandenBerg, Scott R.; Stallcup, William B.; Berger, Mitchel S.; Bergers, Gabriele; Weiss, William A.; Petritsch, Claudia

doi:10.1016/j.ccr.2011.08.011

Cited by 202 publications

(219 citation statements)

References 50 publications

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“…P-values represent the average of at least five samples, P: ns (P40.05), *Po0.05, ***Po0.001, one-way analysis of variance maintenance, and cancer progression. [18][19][20] Moreover, we observed significant epigenetic changes of the methylation status on the promoter region of four genes associated with stemness and self-renewal (FOS, 21 Olig2, 22 RUNX1, 23 and SMAD2 24 ) in DN GBM cells treated with TMZ (Supplementary Figure S4B). These results provide new clues regarding the mechanisms of TMZ-mediated GSC amplification and require further investigation.…”

Section: Resultsmentioning

confidence: 85%

Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

et al. 2014

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Glioblastoma multiforme patients have a poor prognosis due to therapeutic resistance and tumor relapse. It has been suggested that gliomas are driven by a rare subset of tumor cells known as glioma stem cells (GSCs). This hypothesis states that only a few GSCs are able to divide, differentiate, and initiate a new tumor. It has also been shown that this subpopulation is more resistant to conventional therapies than its differentiated counterpart. In order to understand glioma recurrence post therapy, we investigated the behavior of GSCs after primary chemotherapy. We first show that exposure of patient-derived as well as established glioma cell lines to therapeutic doses of temozolomide (TMZ), the most commonly used antiglioma chemotherapy, consistently increases the GSC pool over time both in vitro and in vivo. Secondly, lineage-tracing analysis of the expanded GSC pool suggests that such amplification is a result of a phenotypic shift in the non-GSC population to a GSC-like state in the presence of TMZ. The newly converted GSC population expresses markers associated with pluripotency and stemness, such as CD133, SOX2, Oct4, and Nestin. Furthermore, we show that intracranial implantation of the newly converted GSCs in nude mice results in a more efficient grafting and invasive phenotype. Taken together, these findings provide the first evidence that glioma cells exposed to chemotherapeutic agents are able to interconvert between non-GSCs and GSCs, thereby replenishing the original tumor population, leading to a more infiltrative phenotype and enhanced chemoresistance. This may represent a potential mechanism for therapeutic relapse.

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Section: Resultsmentioning

confidence: 85%

Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

et al. 2014

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“…The tight association between nonrandom DNA segregation and Wnt ACD implies cell-intrinsic reprogramming of SW480 cells by axitinib. Given that the loss of ACD is critical for tumor initiation and progression (4,19,20), the reestablishment of ACD in cancer cells by axitinib could potentially be a mechanism of tumor suppression.…”

Section: Resultsmentioning

confidence: 99%

Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer

Gharbi

Xing

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic mutations of the Wnt (wingless)/β-catenin pathway are frequently observed in major cancer types. Thus far, however, no therapeutic agent targeting Wnt/β-catenin signaling is available for clinical use. Here we demonstrate that axitinib, a clinically approved drug, strikingly blocks Wnt/β-catenin signaling in cancer cells, zebrafish, and Apc min/+ mice. Notably, axitinib dramatically induces Wnt asymmetry and nonrandom DNA segregation in cancer cells by promoting nuclear β-catenin degradation independent of the GSK3β (glycogen synthase kinase3β)/APC (adenomatous polyposis coli) complex. Using a DARTS (drug affinity-responsive target stability) assay coupled to 2D-DIGE (2D difference in gel electrophoresis) and mass spectrometry, we have identified the E3 ubiquitin ligase SHPRH (SNF2, histone-linker, PHD and RING finger domain-containing helicase) as the direct target of axitinib in blocking Wnt/β-catenin signaling. Treatment with axitinib stabilizes SHPRH and thereby increases the ubiquitination and degradation of β-catenin. Our findings suggest a previously unreported mechanism of nuclear β-catenin regulation and indicate that axitinib, a clinically approved drug, would provide therapeutic benefits for cancer patients with aberrant nuclear β-catenin activation.axitinib | β-catenin | asymmetric cell division | SHPRH

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“…Remarkably, all these ACD regulators identified in Drosophila have homologs in vertebrates and most of them have been linked with various human cancers (Gómez-López et al, 2014). Moreover, a connection between impairment of ACD and tumorigenesis is also emerging in mouse models and human tumors (Chen et al, 2014;Cicalese et al, 2009;Hwang et al, 2014;Ito et al, 2010;Sugiarto et al, 2011;Wu et al, 2007).…”

Section: Introductionmentioning

confidence: 98%

Synergism between canoe and scribble mutations causes tumor-like overgrowth via Ras activation in neural stem cells and epithelia

et al. 2017

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Over the past decade an intriguing connection between asymmetric cell division, stem cells and tumorigenesis has emerged. Neuroblasts, which are the neural stem cells of the Drosophila central nervous system, divide asymmetrically and constitute an excellent paradigm for investigating this connection further. Here we show that the simultaneous loss of the asymmetric cell division regulators Canoe (afadin in mammals) and Scribble in neuroblast clones leads to tumor-like overgrowth through both a severe disruption of the asymmetric cell division process and canoe lossmediated Ras-PI3K-Akt activation. Moreover, canoe loss also interacts synergistically with scribble loss to promote overgrowth in epithelial tissues, here just by activating the Ras-Raf-MAPK pathway. discs large 1 and lethal (2) giant larvae, which are functionally related to scribble, contribute to repress the Ras-MAPK signaling cascade in epithelia. Hence, our work uncovers novel cooperative interactions between all these well-conserved tumor suppressors that ensure tight regulation of the Ras signaling pathway.

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Asymmetry-Defective Oligodendrocyte Progenitors Are Glioma Precursors

Cited by 202 publications

References 50 publications

Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer

Synergism between canoe and scribble mutations causes tumor-like overgrowth via Ras activation in neural stem cells and epithelia

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