A5002102492- Protein Degradation and Inhibitors
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Histone Deacetylase Inhibitors Research
- Sarcoma Diagnosis and Treatment
- RNA modifications and cancer
- Pregnancy and preeclampsia studies
- Fibroblast Growth Factor Research
- CRISPR and Genetic Engineering
- Ubiquitin and proteasome pathways
- Chromatin Remodeling and Cancer
- Mesenchymal stem cell research
- Cancer Genomics and Diagnostics
- Cardiac tumors and thrombi
- Cancer-related molecular mechanisms research
- Cancer, Hypoxia, and Metabolism
- Plant Surface Properties and Treatments
- Peptidase Inhibition and Analysis
- TGF-β signaling in diseases
- Hippo pathway signaling and YAP/TAZ
- Angiogenesis and VEGF in Cancer
- Cancer Risks and Factors
- Epigenetics and DNA Methylation
University Children's Hospital Zurich
2019-2023
Ewing sarcoma (EwS) is a highly metastatic bone cancer characterized by the ETS fusion oncoprotein EWS-FLI1. EwS cells are phenotypically plastic and switch between functionally distinct cell states dependent on EWS-FLI1 fluctuations. Whereas EWS-FLI1high proliferate, EWS-FLI1low migratory invasive. Recently, we reported activation of MRTFB TEAD, effectors RhoA Hippo signalling, upon low EWS-FLI1, orchestrating key steps gene expression program. TEAD its co-activators YAP TAZ commonly...
Abstract Ewing sarcoma is the second most common pediatric bone and soft tissue tumor presenting with an aggressive behavior prevalence to metastasize. The diagnostic translocation t(22;11)(q24;12) leads expression of chimeric oncoprotein EWS-FLI1 which uniquely expressed in all cells maintains their survival. Constant protein turnover regulated by ubiquitin proteasome system. Here, we now identified specific protease 19 (USP19) as a regulator stability using siRNA based screening approach....
Abstract Ewing sarcoma is an aggressive cancer with a defective response to DNA damage leading enhanced sensitivity genotoxic agents. Mechanistically, driven by the fusion transcription factor EWS-FLI1, which reprograms tumor cell epigenome. The nucleosome remodeling and deacetylase (NuRD) complex important regulator of chromatin function, controlling both gene expression repair, has been associated EWS-FLI1 activity. Here, NuRD-focused CRISPR/Cas9 inactivation screen identified helicase...
Oncogenic transcription factors lacking enzymatic activity or targetable binding pockets are typically considered "undruggable". An example is provided by the EWS-FLI1 oncoprotein, whose continuous expression and as factor critically required for Ewing sarcoma tumor formation, maintenance, proliferation. Because neither upstream nor downstream targets have so far disabled its oncogenic potential, we performed a high-throughput drug screen (HTS), enriched FDA-approved drugs, coupled to Global...
Abstract As the second most common pediatric bone and soft tissue tumor, Ewing sarcoma (ES) is an aggressive disease with a pathognomonic chromosomal translocation t(11;22) resulting in expression of EWS-FLI1, “undruggable” fusion protein acting as transcriptional modulator. EWS-FLI1 rewires cancer cells by activating repressing multitude genes. The role contribution repressed genes remains unknown to date. To address this, we established CRISPR activation system clonal SKNMC cell lines...
<div>Abstract<p>Ewing sarcoma is an aggressive cancer with a defective response to DNA damage leading enhanced sensitivity genotoxic agents. Mechanistically, Ewing driven by the fusion transcription factor EWS-FLI1, which reprograms tumor cell epigenome. The nucleosome remodeling and deacetylase (NuRD) complex important regulator of chromatin function, controlling both gene expression repair, has been associated EWS-FLI1 activity. Here, NuRD-focused CRISPR/Cas9 inactivation...
<div>Abstract<p>Ewing sarcoma is an aggressive cancer with a defective response to DNA damage leading enhanced sensitivity genotoxic agents. Mechanistically, Ewing driven by the fusion transcription factor EWS-FLI1, which reprograms tumor cell epigenome. The nucleosome remodeling and deacetylase (NuRD) complex important regulator of chromatin function, controlling both gene expression repair, has been associated EWS-FLI1 activity. Here, NuRD-focused CRISPR/Cas9 inactivation...
<p>Supplementary Tables 1-14</p>
<p>Supplementary Figures 1-7 and supplementary material methods</p>
<p>Supplementary Figures 1-7 and supplementary material methods</p>
<p>Supplementary Tables 1-14</p>
Abstract Placental growth factor (PlGF) is a pro-angiogenic, N-glycosylated factor, which secreted under pathologic situations. Here, we investigated the regulation of PlGF in response to ionizing radiation (IR) and its role for tumor angiogenesis radiosensitivity. Secretion expression was induced multiple cell lines (medulloblastoma, colon lung adenocarcinoma) irradiation dose- time-dependent manner. Early upregulation secretion primarily observed p53 wild-type cells, whereas cells with...
<p>Supplementary Data supporting results of main manuscript; with other cell lines; control experiments; includes data table Figure S1. PlGF secretion is increased in multiple lines after irradiation. S2. mRNA expression response to IR. S3. P53 a major regulator S4. Generation knockout using CRISPR/Cas9 system. Table Correlation genetic background tumor early IR.</p>
<div>Abstract<p>Placental growth factor (PlGF) is a pro-angiogenic, N-glycosylated factor, which secreted under pathologic situations. Here, we investigated the regulation of PlGF in response to ionizing radiation (IR) and its role for tumor angiogenesis radiosensitivity. Secretion expression was induced multiple cell lines (medulloblastoma, colon lung adenocarcinoma) irradiation dose- time-dependent manner. Early upregulation secretion primarily observed p53 wild-type cells,...
<p>Supplementary Data supporting results of main manuscript; with other cell lines; control experiments; includes data table Figure S1. PlGF secretion is increased in multiple lines after irradiation. S2. mRNA expression response to IR. S3. P53 a major regulator S4. Generation knockout using CRISPR/Cas9 system. Table Correlation genetic background tumor early IR.</p>
<div>Abstract<p>Placental growth factor (PlGF) is a pro-angiogenic, N-glycosylated factor, which secreted under pathologic situations. Here, we investigated the regulation of PlGF in response to ionizing radiation (IR) and its role for tumor angiogenesis radiosensitivity. Secretion expression was induced multiple cell lines (medulloblastoma, colon lung adenocarcinoma) irradiation dose- time-dependent manner. Early upregulation secretion primarily observed p53 wild-type cells,...
Ewing sarcoma is an aggressive pediatric bone and soft tissue tumor driven by the expression of a fusion oncoprotein named EWS-FLI1, which acts as oncogenic transcription factor. Tumor cells are strictly dependent on continuous protein, since downregulation EWS-FLI1 inhibits growth. Therefore, interference with turnover critical for modulation cell proliferation survival. We demonstrated previously that predominantly proteasomal substrate high mediated poly-ubiquitination at one specific...
Abstract Ewing sarcoma is an aggressive pediatric bone and soft tissue tumor driven by the expression of a fusion oncoprotein named EWS-FLI1, which acts as oncogenic transcription factor. Tumor cells are strictly dependent on continuous protein, since downregulation EWS-FLI1 inhibits growth. Therefore, interference with turnover critical for modulation cell proliferation survival. We demonstrated previously that predominantly proteasomal substrate high mediated poly-ubiquitination at one...
Abstract Ewing’s sarcoma is an aggressive pediatric bone and soft-tissue cancer with a pathognomonic chromosomal translocation t(11;22) resulting in expression of EWS-FLI1, “undruggable” fusion protein acting as transcriptional modulator. Identification ranking repressed EWS-FLI1 target genes essential for cell survival will potentially provide much-needed insights to develop novel therapeutic strategies. We performed CRISPR activation (CRISPRa) dropout screen Ewing cells. generated clonal...
Abstract Ewing sarcoma tumorigenesis is tightly linked to epigenetic deregulation. Indeed, the aberrant fusion transcription factor and tumor driver EWS-FLI1 produces extensive rewiring of cancer cell epigenome. At enhancers containing canonical ETS motifs, protein represses gene expression but, when binding GGAA repeats, induces by recruiting activating regulators such as acetyltransferase p300 BAF chromatin remodeling complex. The nucleosome deacetylase (NuRD) complex an ATP-dependent...