Homo sapiens
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PROVIDER: PRJNA307251 | ENA |
REPOSITORIES: ENA
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Project description:Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth
| PRJNA338981 | ENA
Project description:Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth [ChIP-Seq]
| PRJNA342432 | ENA
Project description:Cell plasticity is a crucial hallmark leading to cancer metastasis. Upregulation of Rho/ROCK pathway drives actomyosin contractility, protrusive forces and contributes to the occurrence of highly invasive amoeboid cells in tumors. Cancer stem cells are similarly associated with metastasis, but how these populations arise in tumors is not fully understood. Here we show that the novel oncogene RASSF1C drives mesenchymal to amoeboid transition and stem cell attributes in breast cancer cells. Mechanistically, RASSF1C activates Rho/ROCK via SRC mediated RhoGDI inhibition, resulting in generation of actomyosin contractility. Moreover, we demonstrate that amoeboid cells display the cancer stem cell markers CD133, ALDH1 and the pluripotent marker Nanog; are accompanied by higher invasive potential in vitro and in vivo; and employ extracellular vesicles to transfer the invasive phenotype to target cells and tissue. Importantly, the underlying RASSF1C driven biological processes concur to explain clinical data: namely, methylation of the RASSF1C promoter correlates with better survival in early stage breast cancer patients. Therefore, we propose the use of RASSF1 gene promoter methylation status as a biomarker for patient stratification.
2021-10-07 | PXD026226 | Pride
Project description:We previously identified a gene signature predicted to regulate the epithelial-mesenchymal transition (EMT) in both epithelial tissue stem cells and breast cancer cells. A phenotypic RNA interference (RNAi) screen identified the genes within this 140-gene signature that promoted the conversion of mesenchymal epithelial cell adhesion molecule-negative (EpCAM-) breast cancer cells to an epithelial EpCAM+/high phenotype. The screen identified 10 of the 140 genes whose individual knockdown was sufficient to promote EpCAM and E-cadherin expression. Among these 10 genes, RNAi silencing of the SWI/SNF chromatin-remodeling factor Smarcd3/Baf60c in EpCAM- breast cancer cells gave the most robust transition from the mesenchymal to epithelial phenotype. Conversely, expression of Smarcd3/Baf60c in immortalized human mammary epithelial cells induced an EMT. The mesenchymal-like phenotype promoted by Smarcd3/Baf60c expression resulted in gene expression changes in human mammary epithelial cells similar to that of claudin-low triple-negative breast cancer cells. These mammary epithelial cells expressing Smarcd3/Baf60c had upregulated Wnt5a expression. Inhibition of Wnt5a by either RNAi knockdown or blocking antibody reversed Smarcd3/Baf60c-induced EMT. Thus, Smarcd3/Baf60c epigenetically regulates EMT by activating WNT signaling pathways. sampleXreference
2013-08-19 | E-GEOD-40145 | biostudies-arrayexpress
Project description:We previously identified a gene signature predicted to regulate the epithelial-mesenchymal transition (EMT) in both epithelial tissue stem cells and breast cancer cells. A phenotypic RNA interference (RNAi) screen identified the genes within this 140-gene signature that promoted the conversion of mesenchymal epithelial cell adhesion molecule-negative (EpCAM-) breast cancer cells to an epithelial EpCAM+/high phenotype. The screen identified 10 of the 140 genes whose individual knockdown was sufficient to promote EpCAM and E-cadherin expression. Among these 10 genes, RNAi silencing of the SWI/SNF chromatin-remodeling factor Smarcd3/Baf60c in EpCAM- breast cancer cells gave the most robust transition from the mesenchymal to epithelial phenotype. Conversely, expression of Smarcd3/Baf60c in immortalized human mammary epithelial cells induced an EMT. The mesenchymal-like phenotype promoted by Smarcd3/Baf60c expression resulted in gene expression changes in human mammary epithelial cells similar to that of claudin-low triple-negative breast cancer cells. These mammary epithelial cells expressing Smarcd3/Baf60c had upregulated Wnt5a expression. Inhibition of Wnt5a by either RNAi knockdown or blocking antibody reversed Smarcd3/Baf60c-induced EMT. Thus, Smarcd3/Baf60c epigenetically regulates EMT by activating WNT signaling pathways.
2013-08-19 | GSE40145 | GEO
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: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
Project description:Glioblastoma (GB) is one of the deadliest types of human cancer. Recurrence after chemoradiation is mostly caused by regrowth of highly invasive and resistant cells. There is an urgent need to better understand the underlying GB mechanisms of chemoradiation resistance and tumor spreading. Using a combination of transcriptomic analysis, longitudinal imaging, organotypic cultures, functional assays, animal studies and clinical data analyses, we demonstrated that chemoradiation and brain vasculature induce a transition to an invasive functional cell state that we named VC-Resist. Better cell survival, G2M-arrest, senescence/stemness pathways’ induction and YAP activation make this GB cell state more resistant to therapy. Notably, these persister GB cells are highly vessel co-opting, allowing homing to the perivascular niche, which in turn increases their transition to this cell state. These findings demonstrate how vessel co-option, the perivascular niche, and GB cell plasticity jointly drive resistance during GB recurrence.
2024-01-01 | GSE218860 | GEO
Project description:The paper describes a model of glioblastoma.
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This model is described in the article:
Modeling the Treatment of Glioblastoma Multiforme and Cancer Stem Cells with Ordinary Differential Equations
Kristen Abernathy and Jeremy Burke BMC
Computational and Mathematical Methods in Medicine Volume 2016, Article ID 1239861, 11 pages
Abstract:
Despite improvements in cancer therapy and treatments, tumor recurrence is a common event in cancer patients. One explanation of recurrence is that cancer therapy focuses on treatment of tumor cells and does not eradicate cancer stem cells (CSCs). CSCs are postulated to behave similar to normal stem cells in that their role is to maintain homeostasis. That is, when the population of tumor cells is reduced or depleted by treatment, CSCs will repopulate the tumor, causing recurrence. In this paper, we study the application of the CSC Hypothesis to the treatment of glioblastoma multiforme by immunotherapy. We extend the work of Kogan et al. (2008) to incorporate the dynamics of CSCs, prove the existence of a recurrence state, and provide an analysis of possible cancerous states and their dependence on treatment levels.
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2019-07-24 | BIOMD0000000757 | BioModels
Project description:The gene expression profiles of two groups of triplicate human glioblastoma (GBM) xenografts grown in immunodeficient rats were compared. The first group of xenografts was derived from a patient biopsy with Epidermal Growth Factor Receptor (EGFR) amplification which grows highly invasive and is independent of angiogenesis. The second group was obtained by introducing a dominant-negative EGFR mutant into the tumor cells, leading to a progression of the tumors to an angiogenic phenotype associated with a transition from a proneural to a mesenchymal GBM molecular subtype.
2017-07-05 | E-MTAB-4898 | biostudies-arrayexpress