Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA151803 | ENA |
REPOSITORIES: ENA
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Project description:CD99 is a transmembrane protein, whose expression is constantly associated to EwingM-bM-^@M-^Ys Sarcoma (EWS), a class of pediatric bone tumors with particular poor prognosis. We previously reported that engagement of CD99 leads to massive and rapid EWS cell death through a non-canonical path. Here we report that death occurs through a novel mechanism starting from classical apoptotic features, such as phosphatydilserine exposure on cell surface and mitochondrial depolarization and ending with massive cytoplasmic hypervacuolization (autophagosomes and micropinosomes). Mechanistically, CD99 induces upregulation of IGFI-R and RAS and rapid MDM2 degradation, which leads to p53 reactivation. We propose that upon CD99 engagement and subsequent p53 reactivation, the EWS-ets oncogene becomes insufficient to sustain EWS transformation; in this context, up-regulated RAS, deprived of a cooperating oncogenic stimulus, might contribute to the delivery of fatal rather than pro-survival signal. The most CD99-responsive EWS cells have either wild type or transcriptional active P53, though mutated, and greatly benefit from MDM2 degradation. Due to the low rate of P53 inactivating mutations in EWS patients, these findings sustain CD99-targeting with specific MAbs either to directly kill EWS cells or to increase sensitivity to chemotherapy. By recruiting also RAS, CD99 delivers a signal which exceeds that of drugs designed exclusive to reactivate p53 functions, besides being easily druggable Ewing Sarcoma cell lines 6647 control or treated with the anti-CD99 0662 MAb were profiled to discover mechanisms related to CD99 targeting. Treated cells were compared to control cells after 30, 60 and 120 minutes of exposure to 0662 (10M-BM-5g/ml); all treatments are in duplicate.
2015-02-01 | E-GEOD-36097 | biostudies-arrayexpress
Project description:CD99 is a transmembrane protein, whose expression is constantly associated to Ewing’s Sarcoma (EWS), a class of pediatric bone tumors with particular poor prognosis. We previously reported that engagement of CD99 leads to massive and rapid EWS cell death through a non-canonical path. Here we report that death occurs through a novel mechanism starting from classical apoptotic features, such as phosphatydilserine exposure on cell surface and mitochondrial depolarization and ending with massive cytoplasmic hypervacuolization (autophagosomes and micropinosomes). Mechanistically, CD99 induces upregulation of IGFI-R and RAS and rapid MDM2 degradation, which leads to p53 reactivation. We propose that upon CD99 engagement and subsequent p53 reactivation, the EWS-ets oncogene becomes insufficient to sustain EWS transformation; in this context, up-regulated RAS, deprived of a cooperating oncogenic stimulus, might contribute to the delivery of fatal rather than pro-survival signal. The most CD99-responsive EWS cells have either wild type or transcriptional active P53, though mutated, and greatly benefit from MDM2 degradation. Due to the low rate of P53 inactivating mutations in EWS patients, these findings sustain CD99-targeting with specific MAbs either to directly kill EWS cells or to increase sensitivity to chemotherapy. By recruiting also RAS, CD99 delivers a signal which exceeds that of drugs designed exclusive to reactivate p53 functions, besides being easily druggable
2015-02-01 | GSE36097 | GEO
Project description:Ewing sarcoma (EWS) is an aggressive pediatric bone tumor characterized by unmet clinical needs and an incompletely understood epigenetic heterogeneity. Here we considered CD99, a major surface molecule hallmark of EWS malignancy. Fluctuations of CD99 expression strongly impair cell dissemination, differentiation, and death. CD99 is also loaded within extracellular vesicles (EVs) and the delivery of CD99 positive or CD99 negative EVs dynamically exerts oncogenic or oncosuppressive functions to recipient cells, respectively. We undertook mass spectrometry and functional annotation analysis to investigate the consequences of CD99 silencing on the proteomic landscape of EWS cells and related EVs. Our data demonstrate that i. the decrease of CD99 leads to major changes in the proteomic profile of EWS cells and EVs; ii. intracellular and extracellular compartments display two distinct signatures of differentially expressed proteins; iii. proteomic changes converge to the modulation of cell migration and immune-modulation biological processes; iv. CD99-silenced cells and related EVs are characterized by a migration-suppressive, pro-immunostimulatory proteomic profile. Overall, our data provide a novel source of CD99-associated protein biomarkers to be considered for further validation as mediators of EWS malignancy and as EWS disease liquid biopsy markers.
2024-05-22 | PXD046846 | Pride
Project description:Affymetrx U95Av2 GeneChip hybridizations, RNA extracted from primary human pediatric alveolar (aRMS) and embryonal (eRMS) rhabdomyosarcoma, plus primary pediatric Ewing's sarcoma (EWS) Keywords = pediatric sarcoma Keywords = Ewing's sarcoma Keywords = rhabdomyosarcoma Keywords: other
2004-03-13 | GSE967 | GEO
Project description:Comparison of expression profiling from Ewing's sarcoma tumor specimen to Ewing's sarcoma cell lines
2008-03-26 | E-MEXP-1142 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE31185: The human Ewing's Sarcoma oncoprotein EWS-FLI1 causes developmental defects in zebrafish embryos GSE31186: The human Ewing's Sarcoma oncoprotein EWS-FLI1 causes Ewing's-type tumors in zebrafish Refer to individual Series
2011-11-01 | E-GEOD-31217 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE20355: BAC-microarrays aCGH data from 67 Ewing's Sarcoma tumor samples and 16 Ewing's Sarcoma cell lines GSE20356: Evaluation of copy number alterations in the Ewing's Sarcoma cell line SKES1 with Affymetrix 500k SNP microarray GSE20357: Expression data from DTL silenced-Ewing Sarcoma's cell lines along with their controls Refer to individual Series
2011-07-31 | E-GEOD-20368 | biostudies-arrayexpress
Project description:Ewing sarcoma (EWS) is an aggressive mesenchymal tumor with unmet clinical need and significant social impacts on children, adolescents and young adults. CD99, a hallmark surface molecule of EWS, participates in crucial biological processes including cell migration, differentiation and death. EWS cells can release CD99 through exosomes, specialized extracellular vesicles with major cell communication roles. Here we show that, as a consequence of CD99 silencing, EWS cells deliver exosomes with oncosuppressive functions which significantly reduce tumor aggressiveness. These CD99-lacking microvesicles modulate gene expression of the EWS recipient cells, reduce proliferation and migration, in turn inducing a more differentiated less malignant phenotype. The most relevant effects were detected on the AP-1 signaling pathway whose regulation was found to be dependent on the specific cargo loaded in vesicles after CD99 shutdown. Investigation of the miRNA content of CD99-deprived exosomes identified miR-199a-3p as a key driver to reverse EWS malignancy in experimental models as well as in clinical specimens. All together our data provide evidence that the abrogation of CD99 in EWS tumor cells leads to produce and release exosomes capable to transfer their antineoplastic effects into the nearby tumor cells, suggesting a novel atypical role for these microvesicles in reversion of malignancy rather than in priming the soil for progression and metastatic seeding. This conceptually innovative approach might offer a new therapeutic opportunity to treat a tumor still refractory to most treatments.
2019-03-22 | GSE128681 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE37370: microRNA expression data from Ewing's sarcoma tumor samples GSE37371: Expression data from Ewing's sarcoma tumor samples Refer to individual Series
2012-06-11 | E-GEOD-37372 | biostudies-arrayexpress
Project description:Genome wide DNA methylation profiling of Rhabdoid tumor of the kidney, Clear cell sarcoma of the kidney, Ewing's sarcoma family of tumors and non-neoplastic kidney. The Illumina Infinium HumanMethylation 27 BeadChip was used to obtain DNA methylation profiles across approximately 27000 CpGs . Samples included 3 Rhabdoid tumor of the kidney, 3 Clear cell sarcoma of the kidney, 3 Ewing's sarcoma family of tumor and 3 non-neoplastic kidney.
2015-06-12 | GSE44847 | GEO