Homo sapiens
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PROVIDER: PRJNA338981 | ENA |
REPOSITORIES: ENA
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Project description:Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth [ChIP-Seq]
| PRJNA342432 | ENA
Project description:Chromatin and transcriptome comparisons of matched NSCs and derivative GSCs reveal activation of WNT5A and an EC signature WNT5A-mediated GdEC differentiation and EC recruitment support the invasive growth of glioma cells in the brain parenchyma.
2016-12-17 | GSE85615 | GEO
Project description:Wnt5a Drives The State Transition To An Invasive Phenotype In Human Glioblastoma Cancer Stem Cells
| PRJNA307251 | ENA
Project description:We have previously shown that Wnt5A drives invasion in melanoma. We have also shown that Wnt5A promotes resistance to therapy designed to target the BRAF(V600E) mutation in melanoma. Here, we show that melanomas characterized by high levels of Wnt5A respond to therapeutic stress by increasing p21 and expressing classical markers of senescence, including positivity for senescence-associated ?-galactosidase (SA-?-gal), senescence-associated heterochromatic foci (SAHF), H3K9Me chromatin marks, and PML bodies. We find that despite this, these cells retain their ability to migrate and invade. Further, despite the expression of classic markers of senescence such as SA-?-gal and SAHF, these Wnt5A-high cells are able to colonize the lungs in in vivo tail vein colony-forming assays. This clearly underscores the fact that these markers do not indicate true senescence in these cells, but instead an adaptive stress response that allows the cells to evade therapy and invade. Notably, silencing Wnt5A reduces expression of these markers and decreases invasiveness. The combined data point to Wnt5A as a master regulator of an adaptive stress response in melanoma, which may contribute to therapy resistance. To better understand the molecular mechanisms governing the response of highly invasive cells to IR as compared to that of poorly invasive cells, we performed microarray analysis of both poorly and highly invasive cells at early and late timepoints after irradiation. Cells were treated with y-irradiation, and RNA was taken at 1 hour, 24 hours and 5 days after irradiation. Microarray analysis was performed using Illumina Human HT-12 ver3 expression arrays, and each time point was compared to RNA from untreated cells.
2015-08-07 | E-GEOD-50004 | biostudies-arrayexpress
Project description:About half of all melanomas harbor a constitutively active mutant BRAFV600E/K kinase that can be selectively inhibited by targeted BRAF inhibitors (BRAFi). While patients treated with BRAFi initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. We observe significant elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein are also elevated in BRAFi-resistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction in levels of endogenous WNT5A in melanoma decreases cell growth, increases apoptosis in response to BRAFi challenge, and decreases the activity of pro-survival AKT signaling. Overexpression of WNT5A conversely promotes melanoma growth and tumorigenesis and activates AKT signaling. Similar to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibits growth, sensitizes melanoma cells to BRAFi, and reduces AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which then acts through FZD7 and RYK to promote AKT signaling, leading to increased growth and therapeutic resistance. Increased WNT5A expression in BRAFi-resistant melanomas also correlates with an associated transcriptional signature, which identifies potential therapeutic targets to reduce clinical resistance to BRAFi. Expression of WNT5A-correlated genes was compared in melanoma cell lines generated to be resistant to PLX4032 and the their associated naïve parental line Basal expression of the WNT5A-correlated genes was also measured in experiments comparing each naïve line to a mixed reference pool containing equal amounts of 47 melanoma cell lines.
2014-03-06 | E-GEOD-55583 | biostudies-arrayexpress
Project description:Ror2 is a member of the Ror-family of receptor tyrosine kinases acting as a receptor for Wnt5a. Wnt5a/Ror2 signaling activates primarily the ß-catenin-independent pathway, which involves various signal mediators, such as Dishevelled, c-Jun N-terminal kinase (JNK), filamin A, c-Src, and Ca2+. Wnt5a/Ror2 signaling has also been shown to inhibit the ß-catenin-dependent pathway. Wnt5a and Ror2 are overexpressed in various types of tumor cells, including osteosarcoma and melanoma cells, resulting in constitutive activation of Wnt5a/Ror2 signaling in a cell-autonomous manner. Constitutively activated Wnt5a/Ror2 signaling has been shown to play important roles in promoting invadopodia formation and invasiveness of tumor cells. However, little is known about the mechanisms underlying these processes. As an attempt to understand the mechanism by which Wnt5a/Ror2 signaling, activated constitutively in osteosarcoma cells, contributes to their highly invasive properties, we performed DNA microarray analysis using a human osteosarcoma cell line, SaOS2.
2017-01-01 | GSE76535 | GEO
Project description:Although fetal bovine serum (FBS) induces the differentiation of cancer stem cells, the underlying mechanism by which this is accomplished has not been clarified. Whether reactive oxygen species affect the differentiation of cancer stem cells in solid tumors as they do in normal stem cells is not known. This study aimed to determine the role of reactive oxygen species in the FBS-induced differentiation of glioblastoma stem cells. We found that FBS activated the oxidative stress response system in glioblastoma stem cells (GSCs). The resulting differentiated cells showed tremendous increases in mitochondrial superoxide and oxygen consumption, accompanied by a loss in stem cell markers and a gain in differentiation markers. The antioxidant N-Acetyl-Cysteine (NAC) inhibited the mitochondrial superoxide increase and prevented the glioblastoma stem cells from differentiating. It appears that FBS-induced cancer stem cell differentiation is caused by mitochondrial activation, which depends on increases in levels of mitochondrial superoxide. GSC11 cells were cultured in stem cell medium or differentiated medium for 1, 3, or 7 days in triplicate. Total RNA was extracted from 12 samples. Microarray experiment and data analysis were done at Dept. of Systems Biology, MDACC (Houston, USA)
2015-02-27 | E-GEOD-28220 | biostudies-arrayexpress
Project description:During embryogenesis, Hepatocyte Growth Factor (HGF) elicits a distinctive morphogenetic program, the invasive growth, by the activation of MET, whose aberrant activation in cancer drives metastatic progression. Aim of this work is to define and characterize the transcriptional signature of invasive growth, and to verify its activation in human cancers. Global expression profiling was carried out on mouse liver stem/progenitor cells (MLP-29) stimulated for different times, one, six and twenty-four hours, in vitro with HGF to define the invasive growth signature. Meta-analysis of human cancer microarray data was carried out to dissect the transcriptional modules of the invasive growth that are aberrantly activated during carcinogenesis of hepatocellular carcinoma. Differential expression analysis identified 2643 regulated genes by HGF, the invasive growth signature, subdivided in 11 gene expression clusters revealing waves of time coded transcriptional regulation. Those waves have been in-silico associated with the regulative role of the transcriptional unit of Rela/Nfkbia and Fos/Jun and biological features recapitulating the physiological invasive growth phenotype observed in cell line, such as cell motility and scattering, cellular proliferation and protection from apoptosis, cytoskeletal rearangement. Genomic meta-analysis on hepatocellular carcinoma identified of a core genes set (323 gene symbols), consistently regulated between MLP-29 and human tumors and significantly associated with cancer aggressiveness and metastasis p.val < 1*10-6, HR=5.404 CI= 2.570-11.365. The invasive growth signature recapitulates the physiopatological program driven by the stimulation of HGF in normal embryonic liver cells and its activity is observed in HCC as well as in several other tumors. This signature is associated with neoplastic progression and reliably predicts human HCC disease outcome, suggesting the involvement of the invasive growth and cancer in cancer progression. These results prompt the future application of anti-met target therapies in HCC and the application of the signature for both prognostic and predictive purposes.
2022-12-30 | GSE43393 | GEO
Project description:Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs). Our group has previously shown that stabilization of HIF2 through genetic deletion or pharmacologic inhibition of the EGLNs mitigates and protects against GI radiotoxicity in mice by improving intestinal crypt stem cell survival. Here we aimed to elucidate the molecular mechanisms by which HIF2 confers GI radioprotection. We developed duodenal organoids from mice, transiently overexpressed non-degradable HIF2, and performed bulk RNA sequencing. Interestingly, HIF2 upregulated known radiation modulators and genes involved in GI homeostasis, including Wnt5a. Non-canonical Wnt5a signaling has been shown by other groups to improve intestinal crypt regeneration in response to injury. Here we show that HIF2 drives Wnt5a expression in multiple duodenal organoid models. Luciferase reporter assays performed in human cells showed that HIF2 directly activates the WNT5A promoter via a hypoxia response element. We then evaluated crypt regeneration using spheroid formation assays. Duodenal organoids that were pre-treated with recombinant Wnt5a had a higher cryptogenic capacity after irradiation, compared to vehicle-treated organoids. Conversely, we found that Wnt5a knockout decreased the cryptogenic potential of intestinal stem cells following irradiation. Treatment with recombinant Wnt5a prior to irradiation rescued the cryptogenic capacity of Wnt5a knockout organoids, indicating that Wnt5a is necessary and sufficient for duodenal radioprotection. Taken together, our results.txt suggest that HIF2 radioprotects the GI tract by inducing Wnt5a expression.
2021-12-15 | GSE186927 | GEO
Project description:Numerous pathways underlie brain invasion by tumors, a critical element underpinning recurrence and lethality in human glioblastomas (hGBMs). The identification of the master factors that elicit these pathways globally, driving invasion altogether, eludes us. We report that high expression levels of non-canonical Wnt5a characterize the most invasive gliomas, epitomize dismal prognosis and discriminate the most infiltrating mesenchymal hGBMs from proneural and classical ones. Exacerbated Wnt5a defines mesenchymal hGBM cells (Wnt5aHigh) possessing prototypical invasiveness and tumor-promoting stem-like characteristics (TPCs), but not their Wnt5aLow siblings. While inhibition of Wnt5a suppresses infiltration in mesenchymal hGBM TPCs, administration or over-expression of Wnt5a elicits the opposite effects, turning on infiltrative “mesenchymal-like” molecular programs in poorly motile, classical hGBM TPCs and Wnt5aLow mesenchymal TPCs, ex vivo and intracranially. Anti-Wnt5a antibodies or antagonist Wnt5a peptides block invasion, increasing survival in clinically relevant intracranial hGBM models. Wnt5a emerges as a master regulator in gliomatous invasion, endowing hGBM TPCs with archetypal, infiltratory transcriptional and functional profiles, providing a unique target to tackle brain invasion by hGBM cancer stem cells.
2017-03-07 | GSE76422 | GEO