Homo sapiens
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PROVIDER: PRJNA148069 | ENA |
REPOSITORIES: ENA
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Project description:Ewing's Sarcoma cell lines were made resistant to different IGF-1R drugs to investigate mechanisms and pathways modulated by the resistance. EWS TC-71 cell line was exposed to increasing concentration to three different anti-IGF-1R drugs (HAb AVE1642, TKI NVP-AEW541, HAb CP-751,871, cell lines named respectively as TC/AVE, TC/AEW or TC/CP) for at least six months. Expression profile of resistant cell variants was compared either singularly for each resistance or commonly vs. parental cell line. Two technical replicates for resistant variants and three biological replicated for parental cell were present.
2012-10-03 | E-GEOD-34027 | biostudies-arrayexpress
Project description:In vitro proteomic expression changes in Ewing sarcoma cell lines after IGF-1R or IGF-1R/IR blockade
| PRJNA312658 | ENA
Project description:Ewing's Sarcoma cell lines were made resistant to different IGF-1R drugs to investigate mechanisms and pathways modulated by the resistance.
2012-10-03 | GSE34027 | GEO
Project description:Ewing sarcoma (EwS) is an aggressive cancer of adolescents in need of effective treatment. Insulin-like growth factor (IGF) 1 is an autocrine growth factor for EwS, but only 10% of patients responded to IGF-1 receptor blockade. Although presumed to originate from mesenchymal progenitors during bone development, targeting of the EwS driver oncogene EWS::FLI1 to the mesenchymal lineage in a mouse model does not result in tumor formation but to skeletal malformations and perinatal death. We report that transient exposure to IGF-1 concentrations mimicking serum levels during puberty reprogrammes limb-derived mesenchymal cells of EWS::FLI1-mutant mice to stable transformation and tumorigenicity. We identify a modular mechanism of IGF-1-driven tumor promotion in the early steps of EwS pathogenesis, in which Yap1 plays a central role. Pharmacologic Yap1/Tead inhibition reverses the transformed phenotype of EWS::FLI1 expressing cells. Our data provide a rationale for combined IGF-1R and YAP/TEAD inhibition in the treatment of EwS patients.
2025-01-31 | GSE269006 | GEO
Project description:Ewing sarcoma (EwS) is an aggressive cancer of adolescents in need of effective treatment. Insulin-like growth factor (IGF) 1 is an autocrine growth factor for EwS, but only 10% of patients responded to IGF-1 receptor blockade. Although presumed to originate from mesenchymal progenitors during bone development, targeting of the EwS driver oncogene EWS::FLI1 to the mesenchymal lineage in a mouse model does not result in tumor formation but to skeletal malformations and perinatal death. We report that transient exposure to IGF-1 concentrations mimicking serum levels during puberty reprogrammes limb-derived mesenchymal cells of EWS::FLI1-mutant mice to stable transformation and tumorigenicity. We identify a modular mechanism of IGF-1-driven tumor promotion in the early steps of EwS pathogenesis, in which Yap1 plays a central role. Pharmacologic Yap1/Tead inhibition reverses the transformed phenotype of EWS::FLI1 expressing cells. Our data provide a rationale for combined IGF-1R and YAP/TEAD inhibition in the treatment of EwS patients.
2025-01-31 | GSE269004 | GEO
Project description:We performed ChIPseq on histone modification marks, transcriptional factors and chromatin architectural proteins in TC-32 and TC-71 Ewing sarcoma cell lines.
2019-08-07 | GSE115250 | GEO
Project description:Ewing Sarcoma is caused by a pathognomonic genomic translocation that places an N-terminal EWSR1 gene in approximation with one of several ETS genes (typically FLI1). This aberration, in turn, alters the transcriptional regulation of more than five hundred genes and perturbs a number of critical pathways that promote oncogenesis, cell growth, invasion, and metastasis. Among them, translocation-mediated up-regulation of the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) are of particular importance since they work in concert to facilitate IGF-1R expression and ligand-induced activation, respectively, of proven importance in ES transformation. When used as a single agent in Ewing sarcoma therapy, IGF-1R or mTOR inhibition leads to rapid counter-regulatory effects that blunt the intended therapeutic purpose. Therefore, identify new mechanisms of resistance that are used by Ewing sarcoma to evade cell death to single-agent IGF-1R inhibition might suggest a number of therapeutic combinations that could improve its clinical activity. TC32 and TC71 ES clones with acquired resistance to OSI-906 or NVP-ADW-742 were generated by maintaining the corresponding parental cell lines with increasing concentrations of the agents (up to 2.3 μM for OSI-906, 1.5 μM for NVP-ADW-742) for 7 months. All parental and acquired drug resistant cell lines were tested twice per year for mycoplasma contamination using the MycoAlert Detection Kit (Lonza Group Ltd.) according to the manufacturerâs protocol and validated using short-tandem repeat fingerprinting with an AmpFLSTR Identifier kit as previously described. Herein, we determine subtle differences in acquired mechanism of resistance by two promising small molecule inhibitors of IGF-1R/IR-α. OSI-906, which inhibits IGF-1R and IR, and NVP-ADW-742, which inhibits only IGF-1R, were evaluated using in vitro assays to decipher the mechanism(s) by which IGF-1R inhibition induces drug resistance in Ewing sarcoma cells. The preparation of extracted proteins from sensitive and acquired resistant Ewing sarcoma cells to OSI-906 and NVP-ADW-742 for reverse-phase protein lysate array (RPPA) analysis were prepared using the same array. Lysates were processed, spotted onto nitrocellulose-coated FAST slides, probed with 115 validated primary antibodies, and detected using a DakoCytomation-catalyzed system with secondary antibodies. MicroVigene software program (VigeneTech) was used for automated spot identification, background correction, and individual spot-intensity determination. Expression data was normalized for possible unequal protein loading, taking into account the signal intensity for each sample for all antibodies tested. Log2 values were media-centered by protein to account for variability in signal intensity by time and were calculated using the formula log2 signal â log2 median. Principal component analysis was used to check for a batch effect and feature-by-feature two-sample t-tests were used to assess differences between sensitive and resistant cell lines to drug treatments. We also used feature-by-feature one-way analysis of variance (ANOVA) followed by the Tukey test to perform pair comparisons for all groups. Beta-uniform mixture models were used to fit the resulting p value distributions to adjust for multiple comparisons. The cutoff p values and number of significant proteins were computed for several different false discovery rates (FDRs). Biostatistical analyses comparing two groups were performed using an unpaired t-test with Gaussian distribution followed by the Welch correction. To distinguish between treatment groups, we used one-way ANOVA with the Geisser-Greenhouse correction. Differences with p values <0.05 were considered significant. Within clustered image maps (CIM), unsupervised double hierarchical clustering used the Pearson correlation distance and Wardâs linkage method as the clustering algorithm to link entities (proteins) and samples.
2016-06-01 | E-GEOD-78121 | biostudies-arrayexpress
Project description:Ewing sarcomas (ES) are highly malignant, osteolytic bone or soft tissue tumors, which are characterized by early metastasis into lung and bone. Genetically, ES are defined by balanced chromosomal EWS/ETS translocations, which give rise to chimeric proteins (EWS-ETS) that generate an oncogenic transcriptional program associated with altered epigenetic marks throughout the genome. By use of an inhibitor (JQ1) blocking BET bromodomain binding proteins (BRDs) we strikingly observed a strong down-regulation of the predominant EWS-ETS protein EWS/FLI1 in a dose dependent manner. Microarray analysis further revealed JQ1 treatment to block a typical ES associated expression program. The effect on this expression program could be mimicked by RNA interference with BRD3 or BRD4 expression, indicating that the EWS/FLI1 mediated expression profile is at least in part mediated via such epigenetic readers. Consequently, contact dependent and independent proliferation of different ES lines was strongly inhibited. Mechanistically, treatment of ES resulted in a partial arrest of the cell cycle as well as induction of apoptosis. Tumor development was suppressed dose dependently in a xeno-transplant model in immune deficient mice, overall indicating that ES may be susceptible to treatment with epigenetic inhibitors blocking BET bromodomain activity and the associated pathognomonic EWS-ETS transcriptional program in ES. Ewing sarcoma cell lines A673 and TC-71 were treated for 48 hours with 2 microM JQ1 or DMSO control.
2015-12-08 | E-GEOD-72673 | biostudies-arrayexpress
Project description:The important role of IGF-1R in cancers has been well established. Classical model involves IGF-1/2 binding to IGF-1R, following activation of the PI3K/Akt pathway, thereby promoting cell proliferation, apoptosis inhibition and treatment resistance. While IGF-1R has become a promising target for cancer therapy, clinical disclosures subsequently have been less encouraging. The question is whether targeting IGF/IGF-1R still holds therapeutic potential. Here we show a novel mechanism that knockdown IGF-1R surprisingly triggers cytoplasmic viral RNA sensors MDA5 and RIG-1, leading to mitochondrial apoptosis in cancer. We analyzed MDA5 and RIG-1 in the intestinal epithelium of IGF-1R knockdown mice. Igf1r+/- mice demonstrated higher MDA5 and RIG-1 than WT mice. IGF-1R knockdown-triggered MDA5 and RIG-1 was further analyzed in human cancer and normal cells. Increased MDA5 and RIG-1 were clearly seen in the cytoplasm identified by immunofluoresce in the cells silenced IGF-1R. Block off IGF-1R downstream PI3K/Akt did not impact on MDA5 and RIG-1 expression. IGF-1R knockdown-triggered MDA5 and RIG-1 and their signaling pathways were similar to those of viral RNA mimetic poly(I:C) had. IGF-1R knockdown-triggered MDA5 and RIG-1 led to cancer apoptosis through activation of the mitochondrial pathway. In vivo assay, Igf1r+/- mice strongly resisted AOM-induced colonic tumorigenesis through triggering MDA¬5- and RIG-1-mediated apoptosis. Notably, RIG-I and MDA5-mediated proapoptotic signaling pathway is preferential active in cancer cells. These data suggest that targeting IGF-1R-triggered MDA5 and RIG-1 might have therapeutic potential for cancer treatment.
2019-11-30 | GSE122534 | GEO
Project description:We performed single-cell RNA sequencing of multiple IGF-1R loss-of function mouse mammary tumor models to uncover how IGF-1R signaling regulates intrinsic epithelial cell signaling to suppress metastasis. We identify key pathways necessary for promoting metastasis, determined IGF-1R is required to maintain a metastatic suppressive tumor microenvironment and demonstrate that attenuated epithelial IGF-1R signaling in the MMTV-Wnt1 mouse tumor model is sufficient for metastatic invasion. We further show that adherence between luminal and basal tumor cells is necessary for tumor growth at the secondary site and that reduced IGF-1R signaling in tumor epithelial cells inhibits secondary tumor epithelial cell growth due to dysregulated E-cadherin and P-cadherin and loss of cell-cell adhesion.
2022-11-21 | GSE182236 | GEO