EWS/FLI is a Master Regulator of Metabolic Reprogramming in Ewing Sarcoma

Ewing sarcoma is a bone malignancy driven by a translocation event resulting in the fusion protein EWS/FLI1 (EF). EF functions as an aberrant and oncogenic transcription factor that misregulates the expression of thousands of genes. Previous work has focused principally on determining important transcriptional targets of EF, as well as characterizing important regulatory partnerships in EF-dependent transcriptional programs. Less is known, however, about EF-dependent metabolic changes or their role in Ewing sarcoma biology. Therefore, the metabolic effects of silencing EF in Ewing sarcoma cells were determined. Metabolomic analyses revealed distinct separation of metabolic profiles in EF-knockdown versus control-knockdown cells. Mitochondrial stress tests demonstrated that knockdown of EF increased respiratory as well as glycolytic functions. Enzymes and metabolites in several metabolic pathways were altered, including de novo serine synthesis and elements of one-carbon metabolism. Furthermore, phosphoglycerate dehydrogenase (PHGDH) was found to be highly expressed in Ewing sarcoma and correlated with worse patient survival. PHGDH knockdown or pharmacologic inhibition in vitro caused impaired proliferation and cell death. Interestingly, PHGDH modulation also led to elevated histone expression and methylation. These studies demonstrate that the translocation-derived fusion protein EF is a master regulator of metabolic reprogramming in Ewing sarcoma, diverting metabolites towar...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Metabolism Source Type: research

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Authors: Krumbholz M, Agaimy A, Stoehr R, Burger M, Wach S, Taubert H, Wullich B, Hartmann A, Metzler M Abstract There is increasing interest in the use of cell-free circulating tumor DNA (ctDNA) as a serum marker for therapy assessment in prostate cancer patients. Prostate cancer is characterized by relatively low numbers of mutations, and, in contrast to many other common epithelial cancers, commercially available single nucleotide mutation assays for quantification of ctDNA are insufficient for therapy assessment in this disease. However, prostate cancer shares some similarity with translocation-affected mesench...
Source: Disease Markers - Category: Laboratory Medicine Tags: Dis Markers Source Type: research
ConclusionsThis analysis of risk for cancer among Ewing sarcoma patients and their relatives indicates evidence for some increased cancer predisposition in this population which can be used to individualize consideration of potential treatment of patients and screening of patients and relatives.
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: ORIGINAL RESEARCH Source Type: research
, Cañete A Abstract Ewing sarcoma is a rare tumor developed in bone and soft tissues of children and teenagers. This entity is biologically led by a chromosomal translocation, typically including EWS and FLI1 genes. Little is known about Ewing sarcoma predisposition, although the role of environmental factors, ethnicity and certain polymorphisms on Ewing sarcoma susceptibility has been studied during the last few years. Its prevalence among cancer predisposition syndromes has also been thoroughly examined. This review summarizes the available evidence on predisposing factors involved in Ewing sarcoma suscep...
Source: Pathology Oncology Research - Category: Pathology Authors: Tags: Pathol Oncol Res Source Type: research
Conclusion Astroblastoma is an extremely rare CNS tumor. Morphological diagnosis is difficult, as the typical astroblastic rosettes may be present also in other CNS tumors, including some gliomas and ependymomas. In fact, AB can be considered as a morphologic pattern, which can be associated with a spectrum of molecular entities. Total resection is the best treatment; the precise role of chemotherapy and radiotherapy is still debated, particularly for high-grade tumors. We believe that DNA-methylation profiles represents an important instrument for confirming diagnosis, predicting prognosis and better defining the molec...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
ConclusionsTaken together, our results suggest that despite downregulated in EWS samples, this miRNA might represent a secondary genetic alteration derived from the pleiotropic cellular effects of the abnormal EWS/FLI1 transcription factor that does not affect tumor growth but instead, is related with the promotion of tumor invasion, not being suitable for future therapeutic intervention.
Source: Cancer Genetics - Category: Cancer & Oncology Source Type: research
Authors: Lee SY, Lim S, Cho DH Abstract A 16-year-old female with Ewing sarcoma, a very rare disease with poor prognosis in women, was admitted to the hospital with abdominal pain. Diagnostic laparotomy revealed the Ewing sarcoma originating from the extramural uterus. Histological examination yielded positive test results for CD99, vimentin, S-100, eosin 5-maleimide and periodic acid-Shiff. EWS-FLI1 type 1 translocation was confirmed. Fibroblast growth factor receptor (FGFR) 4 (c.1162G> A) and HRas proto-oncogene (HRAS; c.182A> G) mutations were also detected. At eight months following complete remission, pe...
Source: Experimental and Therapeutic Medicine - Category: General Medicine Tags: Exp Ther Med Source Type: research
Abstract Ewing sarcoma was first described in 1921 in the Proceedings of the New York Pathological Society by an eminent American pathologist from Cornell named James R. Ewing as a "diffuse endothelioma of bone." Since this initial description, more has been discovered regarding Ewing sarcoma and in the 1980's both Ewing sarcoma and peripheral primitive neuroectodermal tumors due to their similar features and shared identical genetic abnormality were grouped into a class of cancers entitled Ewing sarcoma family of tumors (ESFTs). Ewing sarcoma is the second most common pediatric osseous malignancy follow...
Source: Translational Research : the journal of laboratory and clinical medicine - Category: Laboratory Medicine Authors: Tags: Transl Res Source Type: research
Abstract Desmoplastic Small Round Cell Tumor (DSRCT) is a rare sarcoma tumor of adolescence and young adulthood, which harbors a recurrent chromosomal translocation between the Ewing's sarcoma gene (EWSR1) and the Wilms' tumor suppressor gene (WT1). Patients usually develop multiple abdominal tumors with liver and lymph node metastasis developing later. Survival is poor using a multimodal therapy that includes chemotherapy, radiation and surgical resection, new therapies are needed for better management of DSRCT. Triggering cell apoptosis is the scientific rationale of many cancer therapies. Here, we characterized...
Source: Neoplasia - Category: Cancer & Oncology Authors: Tags: Neoplasia Source Type: research
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Source: Asian Pacific Journal of Cancer Prevention - Category: Cancer & Oncology Tags: Asian Pac J Cancer Prev Source Type: research
EWS–FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma Nature 555, 7696 (2018). doi:10.1038/nature25748 Authors: Aparna Gorthi, July Carolina Romero, Eva Loranc, Lin Cao, Liesl A. Lawrence, Elicia Goodale, Amanda Balboni Iniguez, Xavier Bernard, V. Pragathi Masamsetti, Sydney Roston, Elizabeth R. Lawlor, Jeffrey A. Toretsky, Kimberly Stegmaier, Stephen L. Lessnick, Yidong Chen &Alexander J. R. Bishop Ewing sarcoma is an aggressive paediatric cancer of the bone and soft tissue. It results from a chromosomal translocation, predominantly t(11;22)(q24:q12), that fus...
Source: Nature - Category: Research Authors: Tags: Letter Source Type: research
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