Proteomic Comparison Of DSRCT, Normal Mesenteric Tissues and ES
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ABSTRACT:
PROVIDER: PRJNA428300 | ENA |
REPOSITORIES: ENA
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Project description:Desmoplastic small round cell tumor (DSRCT) is an aggressive malignancy that occurs predominantly in young adult males and is characterized by abdominopelvic sarcomatosis exhibiting multi-lineage cellular nests of epithelial, muscular, mesenchymal, and neural differentiation admixed with desmoplastic stroma. Prior to the recognition of the disease as a distinct clinical entity, DSRCT was invariably misclassified as poorly differentiated atypical cancer of the testes, ovary, mesentery, or gastrointestinal tract, and the chemotherapies used for those malignancies elicited poor clinical response. As previously reported, a tectonic shift in the treatment of these patients occurred after researchers made two astute observations: 1) DSRCT microscopically resembles other small round “blue cell” sarcoma subtypes (e.g., ES, rhabdomyosarcoma, synovial sarcoma), and 2) DSRCT and ES have the same N-terminal EWSR1 fusion partner. Proteomic analysis using a reverse-phase protein lysate array (RPPA) was used to elucidate biomarkers that distinguish DSRCT from adjacent normal tissue and Ewing sarcoma. This proteomic analysis revealed novel proteins, such as the androgen receptor and Syk, that may be susceptible to drug targeting, as well as oncogenic pathways like Akt-PI3K that are highly expressed in DSRCT.
2020-12-31 | GSE108687 | GEO
Project description:Desmoplastic small round cell tumor (DSRCT) is a rare pediatric cancer caused by the EWSR1-WT1 fusion oncogene. Despite initial response to chemotherapy, DSRCT has a recurrence rate of over 80% leading to poor patient prognosis with a 5-year survival rate of only 15-25%. Owing to the rarity of DSRCT, sample scarcity is a barrier to understanding DSRCT biology and developing effective therapies. Here, we performed RNA-sequencing on a novel pair of primary and recurrent DSRCT tumors harvested from the same patient 5-years apart. To gain insights into gene expression alterations associated with recurrence, we performed pathway analysis on Gene Ontology Biological Processes and KEGG pathways. Upregulated pathways in the recurrent tumor included DNA repair and mRNA splicing related pathways, while downregulated pathways included immune system function and focal adhesion. We further examined the expression of previously identified EWSR1-WT1 regulated targets, a large number of which were enriched in the recurrent tumor. Overall, this study provides novel understanding of DSRCT biology and a new RNA-seq data set to advance future studies.
2023-07-19 | GSE230603 | GEO
Project description:The object of this study is to identify the molecular signature underlying the therapeutic potential of N3-induced growth arrest in Desmoplastic Small Round Cell Tumor (DSRCT). The molecular hallmark of DSRCT is the EWS-WT1 fusion protein formed by chromosomal translocations found in DSRCT. The N-terminal transactivation domain of EWS is fused to the C-terminal DNA binding domain of WT1, creating an oncogenic transcription factor. We have recently discovered that addition of N3 supplement to growing DSRCT cells leads to a rapid cessation of cell growth.
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2022-05-20 | PXD029979 | Pride
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Project description:DSRCT is an aggressive, often fatal, sarcoma subtype that usually present in post-pubertal adolescents and young adults. Though the pathognomonic EWSR1-WT1 fusion protein is responsible for tumorigenesis, the androgen receptor (AR) has been suggested as a key contributor to tumor survival and growth. Reverse-phase protein lysate arrays (RPPA) were used to identify new drug targets in DSRCT not present in Ewing sarcoma, a close molecular cousin that shares an EWSR1 N-terminus chimeric partner. Among the 151 proteins analyzed, the AR protein was the most differentially expressed protein, which led to follow-on studies to investigate its role in DSRCT survival and growth in cell lines, xenografts, and patient-derived tumor explants (PDXs), which retain the best fidelity to their human tumor counterparts. Modern-day 2nd-generation AR antagonists were tested for preclinical antitumor activity, in addition to novel AR-directed antisense oligonucleotides that rapidly suppress post-transcriptional activity. Our research demonstrates an important role for the AR in promoting tumor growth and survival in preclinical DSRCT models. Given the widespread availability of safe, orally administered FDA-approved agents used for prostate cancer, such as abiraterone or enzalutamide that potently block AR steroidogenesis or intracellular AR signaling, one could quickly evaluate their effect in DSRCT in phase 2 trials.
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