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Desmoplastic small round cell tumor cancer stem cell-like cells resist chemotherapy but remain dependent on the EWSR1-WT1 oncoprotein.

ABSTRACT: Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive pediatric cancer driven by the EWSR1-WT1 fusion oncogene. Combinations of chemotherapy, radiation and surgery are not curative, and the 5-years survival rate is less than 25%. One potential explanation for refractoriness is the existence of a cancer stem cell (CSC) subpopulation able escape current treatment modalities. However, no study to-date has examined the role of CSCs in DSRCT or established in vitro culture conditions to model this subpopulation. In this study, we investigated the role of stemness markers in DSRCT survival and metastasis, finding that elevated levels of SOX2 and NANOG are associated with worse survival in sarcoma patients and are elevated in metastatic DSRCT tumors. We further develop the first in vitro DSRCT CSC model which forms tumorspheres, expresses increased levels of stemness markers (SOX2, NANOG, KLF4, and OCT4), and resists doxorubicin chemotherapy treatment. This model is an important addition to the DSRCT tool kit and will enable investigation of this critical DSRCT subpopulation. Despite lower sensitivity to chemotherapy, the DSRCT CSC model remained sensitive to knockdown of the EWSR1-WT1 fusion protein, suggesting that future therapies directed against this oncogenic driver have the potential to treat both DSRCT bulk tumor and CSCs.

SUBMITTER: Magrath JW

PROVIDER: S-EPMC9732033 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Desmoplastic small round cell tumor cancer stem cell-like cells resist chemotherapy but remain dependent on the EWSR1-WT1 oncoprotein.

Magrath Justin W JW Kang Hong-Jun HJ Hartono Alifiani A Espinosa-Cotton Madelyn M Somwar Romel R Ladanyi Marc M Cheung Nai-Kong V NV Lee Sean B SB

Frontiers in cell and developmental biology 20221125

Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive pediatric cancer driven by the <i>EWSR1-WT1</i> fusion oncogene. Combinations of chemotherapy, radiation and surgery are not curative, and the 5-years survival rate is less than 25%. One potential explanation for refractoriness is the existence of a cancer stem cell (CSC) subpopulation able escape current treatment modalities. However, no study to-date has examined the role of CSCs in DSRCT or established <i>in vitro</i> cultur ...[more]

PMID: 36506091

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Project description:Desmoplastic small round cell tumor (DSRCT) is a highly aggressive cancer predominantly occurring in young male adolescents. It mainly arises at sites lined by mesothelium, such as the abdominal cavity, and is driven by the pathognomonic EWSR1::WT1 fusion oncoprotein. The dismal survival rates (5–20%) have not significantly improved since its first description in 1989, also due to a lack of comprehensive datasets that could shed new light on the biology of the disease and uncover novel diagnostic markers and therapeutic targets. Thus, we established genome-wide single-cell RNA-sequencing and bulk proteomic data of in vitro and in vivo-generated EWSR1::WT1 knockdown models and combined them with an original systems-biology-based pipeline including patient data, resulting in a rich resource for discovery analyses. This approach revealed the alpha-2/delta subunit of the voltage-dependent calcium channel complex, CACNA2D2, as a strongly overexpressed direct target of EWSR1::WT1 in DSRCTs, which is regulated by an EWSR1::WT1-bound super-enhancer. Ectopic expression of the main EWSR1::WT1 isoforms in mesothelial cells, the putative cell of origin of DSRCTs, confirmed that EWSR1::WT1 is sufficient to induce super-enhancer formation at the CACNA2D2 locus followed by robust transcription of this gene. Moreover, single-cell and bulk-level analyses on patient samples and cell line-derived xenografts highlighted CACNA2D2 as a critical mediator of the EWSR1::WT1 oncogenic signature. Based on bulk and single-cell transcriptomic data, the computed CACNA2D2 signature could be further utilized to robustly identify DSRCTs in reference sets. Finally, we show that CACNA2D2 is a highly sensitive and specific single biomarker for fast, simple, and cost-efficient diagnosis of DSRCT. Collectively, we established a freely available large-scale multi-omics dataset for this devastating disease and provide a blueprint of how such data can be used to identify a new and clinically relevant diagnostic marker, which may significantly reduce misdiagnoses, and thus improve patient care.

Dataset Information

Desmoplastic small round cell tumor cancer stem cell-like cells resist chemotherapy but remain dependent on the EWSR1-WT1 oncoprotein.

Publications

Desmoplastic small round cell tumor cancer stem cell-like cells resist chemotherapy but remain dependent on the EWSR1-WT1 oncoprotein.

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