RNA sequencing and functional studies of patient-derived cells reveal that neurexin-1 and regulators of this pathway are associated with poor outcomes in Ewing sarcoma
| Autor: | Michael Parry, Mariona Chicon-Bosch, Elizabeth Ann Roundhill, Kenneth S. Rankin, Susan A. Burchill, Alastair Droop, Lee Jeys |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Cell Adhesion Molecules Neuronal Cell Neurexin-1 Antineoplastic Agents Bone Neoplasms Nerve Tissue Proteins Kaplan-Meier Estimate Sarcoma Ewing Biology Patient-derived cells Transcriptome Cell Line Tumor Biomarkers Tumor Tumor Cells Cultured medicine Humans Child Neural Cell Adhesion Molecules Gene Adaptor Proteins Signal Transducing Sequence Analysis RNA Calcium-Binding Proteins Mesenchymal stem cell Cancer General Medicine Prognosis medicine.disease Embryonic stem cell Gene Expression Regulation Neoplastic medicine.anatomical_structure Oncology Doxorubicin Vincristine Cell culture Neoplastic Stem Cells Cancer research Molecular Medicine Original Article Ewing sarcoma stem-like cells Sarcoma Ewing sarcoma |
| Zdroj: | Cellular Oncology (Dordrecht) |
| ISSN: | 2211-3428 |
| Popis: | Purpose The development of biomarkers and molecularly targeted therapies for patients with Ewing sarcoma (ES) in order to minimise morbidity and improve outcome is urgently needed. Here, we set out to isolate and characterise patient-derived ES primary cell cultures and daughter cancer stem-like cells (CSCs) to identify biomarkers of high-risk disease and candidate therapeutic targets. Methods Thirty-two patient-derived primary cultures were established from treatment-naïve tumours and primary ES-CSCs isolated from these cultures using functional methods. By RNA-sequencing we analysed the transcriptome of ES patient-derived cells (n = 24) and ES-CSCs (n = 11) to identify the most abundant and differentially expressed genes (DEGs). Expression of the top DEG(s) in ES-CSCs compared to ES cells was validated at both RNA and protein levels. The functional and prognostic potential of the most significant gene (neurexin-1) was investigated using knock-down studies and immunohistochemistry of two independent tumour cohorts. Results ES-CSCs were isolated from all primary cell cultures, consistent with the premise that ES is a CSC driven cancer. Transcriptional profiling confirmed that these cells were of mesenchymal origin, revealed novel cell surface targets for therapy that regulate cell-extracellular matrix interactions and identified candidate drivers of progression and relapse. High expression of neurexin-1 and low levels of regulators of its activity, APBA1 and NLGN4X, were associated with poor event-free and overall survival rates. Knock-down of neurexin-1 decreased viable cell numbers and spheroid formation. Conclusions Genes that regulate extracellular interactions, including neurexin-1, are candidate therapeutic targets in ES. High levels of neurexin-1 at diagnosis are associated with poor outcome and identify patients with localised disease that will relapse. These patients could benefit from more intensive or novel treatment modalities. The prognostic significance of neurexin-1 should be validated independently. |
| Databáze: | OpenAIRE |
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