pediatric tumor
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NAR Cancer ◽  
2022 ◽  
Vol 4 (1) ◽  
Author(s):  
Garrett T Graham ◽  
Saravana P Selvanathan ◽  
Stefan K Zöllner ◽  
Emily Stahl ◽  
Adam Shlien ◽  
...  

ABSTRACT Ewing sarcoma (EwS) is a small round blue cell tumor and is the second most frequent pediatric bone cancer. 85% of EwS tumors express the fusion oncoprotein EWS-FLI1, the product of a t(11;22) reciprocal translocation. Prior work has indicated that transcription regulation alone does not fully describe the oncogenic capacity of EWS-FLI1, nor does it provide an effective means to stratify patient tumors. Research using EwS cell lines and patient samples has suggested that EWS-FLI1 also disrupts mRNA biogenesis. In this work we both describe the underlying characteristics of mRNA that are aberrantly spliced in EwS tumor samples as well as catalogue mRNA splicing events across other pediatric tumor types. Here, we also use short- and long-read sequencing to identify cis-factors that contribute to splicing profiles we observe in Ewing sarcoma. Our analysis suggests that GC content upstream of cassette exons is a defining factor of mRNA splicing in EwS. We also describe specific splicing events that discriminate EwS tumor samples from the assumed cell of origin, human mesenchymal stem cells derived from bone marrow (hMSC-BM). Finally, we identify specific splicing factors PCBP2, RBMX, and SRSF9 by motif enrichment and confirm findings from tumor samples in EwS cell lines.


2022 ◽  
Vol 6 (1) ◽  
Author(s):  
Safiya Khurshid ◽  
Matias Montes ◽  
Daniel F. Comiskey ◽  
Brianne Shane ◽  
Eleftheria Matsa ◽  
...  

AbstractRhabdomyosarcoma (RMS) is an aggressive pediatric tumor with a poor prognosis for metastasis and recurrent disease. Large-scale sequencing endeavors demonstrate that Rhabdomyosarcomas have a dearth of precisely targetable driver mutations. However, IGF-2 signaling is known to be grossly altered in RMS. The insulin receptor (IR) exists in two alternatively spliced isoforms, IR-A and IR-B. The IGF-2 signaling molecule binds both its innate IGF-1 receptor as well as the insulin receptor variant A (IR-A) with high affinity. Mitogenic and proliferative signaling via the canonical IGF-2 pathway is, therefore, augmented by IR-A. This study shows that RMS patients express increased IR-A levels compared to control tissues that predominantly express the IR-B isoform. We also found that Hif-1α is significantly increased in RMS tumors, portraying their hypoxic phenotype. Concordantly, the alternative splicing of IR adapts to produce more IR-A in response to hypoxic stress. Upon examining the pre-mRNA structure of the gene, we identified a potential hypoxia-responsive element, which is also the binding site for the RNA-binding protein CUG-BP1 (CELF1). We designed Splice Switching Oligonucleotides (SSO) against this binding site to decrease IR-A levels in RMS cell lines and, consequently, rescue the IR-B expression levels. SSO treatment resulted in a significant reduction in cell proliferation, migration, and angiogenesis. Our data shows promising insight into how impeding the IGF-2 pathway by reducing IR-A expression mitigates tumor growth. It is evident that Rhabdomyosarcomas use IR alternative splicing as yet another survival strategy that can be exploited as a therapeutic intervention in conjunction with already established anti-IGF-1 receptor therapies.


2021 ◽  
Author(s):  
E. John P Tokarsky ◽  
Jesse C. Crow ◽  
Lillian M. Guenther ◽  
John Sherman ◽  
Cenny Taslim ◽  
...  

Expression of the fusion oncoprotein EWS/FLI causes Ewing sarcoma, an aggressive pediatric tumor characterized by widespread epigenetic deregulation. These epigenetic changes are targeted by novel lysine specific demethylase-1 (LSD1) inhibitors, which are currently in early phase clinical trials. Single agent targeted therapy often induces resistance, and successful clinical development requires knowledge of resistance mechanisms, enabling the design of effective combination strategies. Here, we used a genome-scale CRISPR-Cas9 loss-of-function screen to identify genes whose knockout (KO) conferred resistance to the LSD1 inhibitor SP-2509 in Ewing sarcoma cell lines. Multiple genes required for mitochondrial electron transport chain (ETC) complexes III and IV function were hits in our screen. We validated this finding using genetic and chemical approaches including CRISPR KO, ETC inhibitors, and mitochondrial depletion. Further global transcriptional profiling revealed that altered complex III/IV function disrupted the oncogenic program mediated by EWS/FLI and LSD1 and blunted the transcriptomic response to SP-2509. These findings demonstrate that mitochondrial dysfunction modulates SP-2509 efficacy and suggest that new therapeutic strategies combining LSD1 with agents which prevent mitochondrial dysfunction may benefit patients with this aggressive malignancy.


2021 ◽  
Vol 11 (12) ◽  
pp. 1286
Author(s):  
Bieke Decaesteker ◽  
Kaat Durinck ◽  
Nadine Van Roy ◽  
Bram De Wilde ◽  
Christophe Van Neste ◽  
...  

Neuroblastoma is a pediatric tumor arising from the sympatho-adrenal lineage and a worldwide leading cause of childhood cancer-related deaths. About half of high-risk patients die from the disease while survivors suffer from multiple therapy-related side-effects. While neuroblastomas present with a low mutational burden, focal and large segmental DNA copy number aberrations are highly recurrent and associated with poor survival. It can be assumed that the affected chromosomal regions contain critical genes implicated in neuroblastoma biology and behavior. More specifically, evidence has emerged that several of these genes are implicated in tumor dependencies thus potentially providing novel therapeutic entry points. In this review, we briefly review the current status of recurrent DNA copy number aberrations in neuroblastoma and provide an overview of the genes affected by these genomic variants for which a direct role in neuroblastoma has been established. Several of these genes are implicated in networks that positively regulate MYCN expression or stability as well as cell cycle control and apoptosis. Finally, we summarize alternative approaches to identify and prioritize candidate copy-number driven dependency genes for neuroblastoma offering novel therapeutic opportunities.


Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5897
Author(s):  
Jikui Guan ◽  
Bengt Hallberg ◽  
Ruth H. Palmer

Neuroblastoma is the most common extracranial solid pediatric tumor, with around 15% childhood cancer-related mortality. High-risk neuroblastomas exhibit a range of genetic, morphological, and clinical heterogeneities, which add complexity to diagnosis and treatment with existing modalities. Identification of novel therapies is a high priority in high-risk neuroblastoma, and the combination of genetic analysis with increased mechanistic understanding—including identification of key signaling and developmental events—provides optimism for the future. This focused review highlights several recent findings concerning chromosomes 1p, 2p, and 11q, which link genetic aberrations with aberrant molecular signaling output. These novel molecular insights contribute important knowledge towards more effective treatment strategies for neuroblastoma.


Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5668
Author(s):  
Laura García-García ◽  
Enrique Fernández-Tabanera ◽  
Saint T. Cervera ◽  
Raquel M. Melero-Fernández de Mera ◽  
Santiago Josa ◽  
...  

Ewing sarcoma is a rare pediatric tumor characterized by chromosomal translocations that give rise to aberrant chimeric transcription factors (e.g., EWSR1-FLI1). EWSR1-FLI1 promotes a specific cellular transcriptional program. Therefore, the study of EWSR1-FLI1 target genes is important to identify critical pathways involved in Ewing sarcoma tumorigenesis. In this work, we focused on the transcription factors regulated by EWSR1-FLI1 in Ewing sarcoma. Transcriptomic analysis of the Ewing sarcoma cell line A673 indicated that one of the genes more strongly upregulated by EWSR1-FLI1 was FEZF1 (FEZ family zinc finger protein 1), a transcriptional repressor involved in neural cell identity. The functional characterization of FEZF1 was performed in three Ewing sarcoma cell lines (A673, SK-N-MC, SK-ES-1) through an shRNA-directed silencing approach. FEZF1 knockdown inhibited clonogenicity and cell proliferation. Finally, the analysis of the FEZF1-dependent expression profile in A673 cells showed several neural genes regulated by FEZF1 and concomitantly regulated by EWSR1-FLI1. In summary, FEZF1 is transcriptionally regulated by EWSR1-FLI1 in Ewing sarcoma cells and is involved in the regulation of neural-specific genes, which could explain the neural-like phenotype observed in several Ewing sarcoma tumors and cell lines.


2021 ◽  
Vol 9 ◽  
Author(s):  
Gloria Pelizzo ◽  
Federica Riva ◽  
Stefania Croce ◽  
Maria Antonietta Avanzini ◽  
Gloria Acquafredda ◽  
...  

The explanation for cancer recurrence still remains to be fully elucidated. Moreover, tumor dormancy, which is a process whereby cells enter reversible G0 cell cycle arrest, appears to be a critical step in this phenomenon. We evaluated the cell cycle proliferation pattern in pediatric tumor-derived mesenchymal stromal cells (MSCs), in order to provide a better understanding of the complex mechanisms underlying cancer dormancy. Specimens were obtained from 14 pediatric patients diagnosed with solid tumors and submitted to surgery. Morphology, phenotype, differentiation, immunological capacity, and proliferative growth of tumor MSCs were studied. Flow cytometric analysis was performed to evaluate the cell percentage of each cell cycle phase. Healthy donor bone marrow-derived mesenchymal stromal cells (BM-MSCs) were employed as controls. It was noted that the DNA profile of proliferating BM-MSC was different from that of tumor MSCs. All BM-MSCs expressed the typical DNA profile of proliferating cells, while in all tumor MSC samples, ≥70% of the cells were detected in the G0/G1 phase. In particular, seven tumor MSC samples displayed intermediate cell cycle behavior, and the other seven tumor MSC samples exhibited a slow cell cycle. The increased number of tumor MSCs in the G0–G1 phase compared with BM-MSCs supports a role for quiescent MSCs in tumor dormancy regulation. Understanding the mechanisms that promote dormant cell cycle arrest is essential in identifying predictive markers of recurrence and to promote a dedicated surgical planning.


2021 ◽  
pp. 1-6
Author(s):  
Max Kahn ◽  
Stanca Iacob ◽  
Sarah E. Bach ◽  
Thomas Russell ◽  
Anthony M. Avellino ◽  
...  

<b><i>Background and Importance:</i></b> Immature teratoma is a known pediatric tumor. However, spinal variants are rare and can present both a diagnostic and therapeutic challenge, particularly regarding aggression as it pertains to extent of resection, likelihood of recurrence and concordant prognosis, and the need and efficacy of adjuvant therapies. <b><i>Clinical Presentation:</i></b> The patient is a 27-day-old female who presented with 10 days of poor feeding, irritability, and progressive hypotonia. Although upon immediate presentation emergency providers’ differential diagnoses included meningitis, inborn error of metabolism, and genetic neurodegenerative disease, a subsequent magnetic resonance (MR) imaging of the total spine revealed a large intradural intramedullary mass extending from the medulla to the thoracic cord at T12. The patient underwent multilevel cervical and thoracic laminectomies/laminoplasty for maximal safe resection. Histopathology revealed mostly mature tissue elements originating from all 3 germ layers, interspersed with foci of immature neuroepithelium, consistent with grade 1 immature teratoma. Following surgical intervention, the patient regained strength and spontaneous movement and underwent physical therapy. Follow-up MR imaging of the total spine was obtained every 3 months, and at 9 months, recurrence was demonstrated, which was successfully treated with chemotherapy. Further surveillance MR imaging of the total spine has demonstrated cystic myelomalacia changes without definite tumor recurrence, at 5-year follow-up. Clinically, the patient has developed scoliosis without weakness, pain, or urinary symptoms. <b><i>Conclusion:</i></b> This case demonstrates an exceptionally rare and unusual variant neoplasm in a neonate and highlights the difficulty of diagnosis and the important role of MR imaging. It also illustrates the importance of gross total resection, the risk of recurrence, and the need for close radiographic follow-up of these lesions. It also provides a useful example of the efficacy of adjuvant chemotherapy in treating recurrence.


2021 ◽  
pp. 1738-1748
Author(s):  
Lieke M. J. van Zogchel ◽  
Nathalie S. M. Lak ◽  
Onno J. H. M. Verhagen ◽  
Ahmed Tissoudali ◽  
Mohammed Gussmalla Nuru ◽  
...  

PURPOSE Liquid biopsies can be used to investigate tumor-derived DNA, circulating in the cell-free DNA (cfDNA) pool in blood. We aimed to develop a droplet digital polymerase chain reaction (ddPCR) assay detecting hypermethylation of tumor suppressor gene RASSF1A as a simple standard test to detect various pediatric tumor types in small volume blood samples and to evaluate this test for monitoring treatment response of patients with high-risk neuroblastoma. METHODS We developed a ddPCR assay to sensitively detect tumor-derived hypermethylated RASSF1A DNA in liquid biopsies. We tested this assay in plasma of 96 patients with neuroblastoma, renal tumors, rhabdomyosarcoma, or Hodgkin lymphoma at diagnosis and in cerebrospinal fluid of four patients with brain tumors. We evaluated the presence of hypermethylated RASSF1A in plasma samples during treatment and follow-up in 47 patients with neuroblastoma treated according to high-risk protocol and correlated results with blood mRNA–based and bone marrow mRNA–based minimal residual disease detection and clinical outcomes. RESULTS The total cfDNA level was significantly higher in patients with metastatic neuroblastoma and nephroblastoma compared with healthy adult and pediatric controls. Hypermethylated RASSF1A was present in 41 of 42 patients with metastatic neuroblastoma and in all patients with nephroblastoma, with the median percentage of 69% and 21% of total RASSF1A, respectively. Hypermethylated RASSF1A levels decreased during therapy and recurred at relapse. CONCLUSION Our findings demonstrate the value of ddPCR-based detection of hypermethylated RASSF1A as a circulating molecular tumor marker in neuroblastoma. Our preliminary investigation of RASSF1A hypermethylation detection in circulating cfDNA of other pediatric tumor entities demonstrates potential as a pan-tumor marker, but requires investigation in larger cohorts to evaluate its use and limitations.


2021 ◽  
Author(s):  
Xinke Xu ◽  
Hongyao Yuan ◽  
Junping Pan ◽  
Wei Chen ◽  
Cheng Chen ◽  
...  

Abstract Background: Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant pediatric tumor of the central nervous system (CNS) with high recurrence and low survival rates that is often misdiagnosed. MicroRNAs (miRNAs) are involved in the tumorigenesis of numerous pediatric cancers, but their roles in AT/RT remain unclear.Methods: In this study, we used miRNA sequencing and gene expression microarrays from patient tissue to study both the miRNAome and transcriptome traits of AT/RT.Results: Our findings demonstrate that 5 miRNAs were up-regulated, 16 miRNAs were down-regulated, 179 mRNAs were up-regulated and 402 mRNAs were down-regulated in AT/RT. The expressions of hsa-miR-17-5p and MAP7 mRNA showed the most significant differences in AT/RT tissues as assayed by qPCR, and analyses using the miRTarBase database identified MAP7 mRNA as a target gene of hsa-miR-17-5p. Conclusions: Our findings suggest that the dysregulation of hsa-miR-17-5p may be a pivotal event in AT/RT and MAP7 miRNAs that may represent potential therapeutic targets and diagnostic biomarkers.


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