Publications by authors named "Olivier Delattre"

264 Publications

Unraveling Ewing sarcoma tumorigenesis originating from patient-derived Mesenchymal Stem Cells.

Cancer Res 2021 Aug 2. Epub 2021 Aug 2.

Laboratory of Genome Dynamics in the Immune System,INSERM, UMR 1163, Imagine Institute for Genetic Diseases

Ewing sarcoma (EwS) is characterized by pathognomonic translocations, most frequently fusing EWSR1 with FLI1. An estimated 30% of EwS tumors also display genetic alterations in STAG2, TP53, or CDKN2A (SPC). Numerous attempts to develop relevant EwS models from primary human cells have been unsuccessful in faithfully recapitulating the phenotypic, transcriptomic and epigenetic features of EwS. In this study, by engineering the t(11;22)(q24;q12) translocation together with a combination of SPC mutations, we generated a wide collection of immortalized cells (EWIma cells) tolerating EWSR1-FLI1 expression from primary mesenchymal stem cells (MSC) derived from an EwS patient. Within this model, SPC alterations strongly favored EwS oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed bona fide features of EwS. EWIma cells presented balanced but also more complex translocation profiles mimicking chromoplexy, which is frequently observed in EwS and other cancers. Collectively, these results demonstrate that bone marrow-derived MSCs are a source of origin for EwS and also provide original experimental models to investigate Ewing sarcomagenesis.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3837DOI Listing
August 2021

Identification of tissue of origin and guided therapeutic applications in cancers of unknown primary using deep learning and RNA sequencing (TransCUPtomics).

J Mol Diagn 2021 Jul 26. Epub 2021 Jul 26.

INSERM U830, Équipe Labellisée Ligue Nationale Contre le Cancer, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, Institut Curie Research Center, Paris, France; Department of Medical Oncology, Institut Curie Hospital, Paris, France. Electronic address:

Cancers of unknown primary (CUP) are metastatic cancers for which the primary tumor is not found despite thorough diagnostic investigations. Multiple molecular assays have been proposed to identify the tissue of origin (TOO) and inform clinical care, however none has been able to combine accuracy, interpretability and easy access for routine use. We developed a classifier tool based on the training of a variational autoencoder (VAE) to predict tissue of origin based on RNA-seq data. We used as training data 20,918 samples corresponding to 94 different categories, including 39 cancer types and 55 normal tissues. The TransCUPtomics classifier was applied to a retrospective cohort of 37 CUP patients, and to 11 prospective patients. TransCUPtomics showed an overall accuracy of 96% on reference data for TOO prediction. The TOO could be identified in 38/48 CUP patients (79%). 8/11 prospective CUP patients (73%) could receive first-line therapy guided by TransCUPtomics prediction with responses observed in most patients. The VAE added further utility by enabling prediction interpretability, and diagnostic predictions could be matched to detection of gene fusions and expressed variants. TransCUPtomics confidently predicted TOO for CUP and enabled tailored treatments leading to significant clinical responses. The interpretability of our approach is a powerful addition to improve the management of CUP patients.
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http://dx.doi.org/10.1016/j.jmoldx.2021.07.009DOI Listing
July 2021

Molecular diagnosis of retinoblastoma by circulating tumor DNA analysis.

Eur J Cancer 2021 Jul 20;154:277-287. Epub 2021 Jul 20.

SiRIC RTOP « Recherche Translationelle en Oncologie Pédiatrique », Translational Research Department, PSL Research University, Institut Curie Research Center, Paris, France; INSERM U830, Equipe Labellisée Ligue Contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France; Department of Translational Research, Institut Curie Research Center, Paris, France; SIREDO Center: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France. Electronic address:

Purpose: The analysis of circulating tumor DNA (ctDNA), a fraction of total cell-free DNA (cfDNA), might be of special interest in retinoblastoma patients. Because the accessibility to tumor tissue is very limited in these patients, either for histopathological diagnosis of suspicious intraocular masses (biopsies are proscribed) or for somatic RB1 studies and genetic counseling (due to current successful conservative approaches), we aim to validate the detection of ctDNA in plasma of non-hereditary retinoblastoma patients by molecular analysis of RB1 gene.

Experimental Design: In a cohort of 19 intraocular unilateral non-hereditary retinoblastoma patients for whom a plasma sample was available at diagnosis, we performed high-deep next-generation sequencing (NGS) of RB1 in cfDNA. Two different bioinformatics/statistics approaches were applied depending on whether the somatic RB1 status was available or not.

Results: Median plasma sample volume was 600 μL [100-1000]; median cfDNA plasma concentration was 119 [38-1980] and 27 [11-653] ng/mL at diagnosis and after complete remission, respectively. In the subgroup of patients with known somatic RB1 alterations (n = 11), seven of nine somatic mutations were detected (median allele fraction: 6.7%). In patients without identified somatic RB1 alterations (n = 8), six candidate variants were identified for seven patients.

Conclusions: Despite small tumor size, blood-ocular barrier, poor ctDNA blood release and limited plasma sample volumes, we confirm that it is possible to detect ctDNA with high-deep NGS in plasma from patients with intraocular non-hereditary retinoblastoma. This may aid in diagnosis of suspicious cases, family genetic counseling or follow-up of residual intraocular disease.
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http://dx.doi.org/10.1016/j.ejca.2021.05.039DOI Listing
July 2021

Plasticity in Neuroblastoma Cell Identity Defines a Noradrenergic-to-Mesenchymal Transition (NMT).

Cancers (Basel) 2021 Jun 10;13(12). Epub 2021 Jun 10.

Institut Curie, PSL Research University, Inserm U830, Equipe Labellisée Ligue Contre le Cancer, 75005 Paris, France.

Neuroblastoma, a pediatric cancer of the peripheral sympathetic nervous system, is characterized by an important clinical heterogeneity, and high-risk tumors are associated with a poor overall survival. Neuroblastoma cells may present with diverse morphological and biochemical properties in vitro, and seminal observations suggested that interconversion between two phenotypes called N-type and S-type may occur. In 2017, two main studies provided novel insights into these subtypes through the characterization of the transcriptomic and epigenetic landscapes of a panel of neuroblastoma cell lines. In this review, we focus on the available data that define neuroblastoma cell identity and propose to use the term noradrenergic (NOR) and mesenchymal (MES) to refer to these identities. We also address the question of transdifferentiation between both states and suggest that the plasticity between the NOR identity and the MES identity defines a noradrenergic-to-mesenchymal transition, reminiscent of but different from the well-established epithelial-to-mesenchymal transition.
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http://dx.doi.org/10.3390/cancers13122904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230375PMC
June 2021

Frequency and Prognostic Impact of Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1).

J Clin Oncol 2021 Jun 11:JCO2100086. Epub 2021 Jun 11.

Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.

Purpose: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact.

Materials And Methods: Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine amplification status (n = 330), mutational profile (n = 191), or both (n = 571).

Results: Genomic amplification (a) was detected in 4.5% of cases (41 out of 901), all except one with amplification (MNA). a was associated with a significantly poorer overall survival (OS) (5-year OS: a [n = 41] 28% [95% CI, 15 to 42]; no-a [n = 860] 51% [95% CI, 47 to 54], [ < .001]), particularly in cases with metastatic disease. mutations (m) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of m and MNA ( < .001). Among 571 cases with known a and m status, a statistically significant difference in OS was observed between cases with a or clonal m versus subclonal m or no alterations (5-year OS: a [n = 19], 26% [95% CI, 10 to 47], clonal m [n = 65] 33% [95% CI, 21 to 44], subclonal m (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively, = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; < .001), a (HR, 2.38; = .004), and clonal (HR, 1.77; = .001) were independent predictors of poor outcome.

Conclusion: Genetic alterations of (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with alterations.
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http://dx.doi.org/10.1200/JCO.21.00086DOI Listing
June 2021

Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden.

Nat Commun 2021 05 28;12(1):3230. Epub 2021 May 28.

St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.

Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.
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http://dx.doi.org/10.1038/s41467-021-23445-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163828PMC
May 2021

Proteomic screens for suppressors of anoikis identify IL1RAP as a promising surface target in Ewing sarcoma.

Cancer Discov 2021 May 21. Epub 2021 May 21.

Michael Smith Genome Science Centre, Brtish Columbia Cancer Agency.

Cancer cells must overcome anoikis (detachment-induced death) to successfully metastasize. Using proteomic screens, we found that distinct oncoproteins upregulate IL-1 receptor accessory protein (IL1RAP) to suppress anoikis. IL1RAP is directly induced by oncogenic fusions of Ewing sarcoma (EwS), a highly metastatic childhood sarcoma. IL1RAP inactivation triggers anoikis and impedes metastatic dissemination of EwS cells. Mechanistically, IL1RAP binds the cell surface system Xc- transporter to enhance exogenous cystine uptake, thereby replenishing cysteine and the glutathione antioxidant. Under cystine depletion, IL1RAP induces cystathionine gamma lyase (CTH) to activate the transsulfuration pathway for de novo cysteine synthesis. Therefore IL1RAP maintains cyst(e)ine and glutathione pools which are vital for redox homeostasis and anoikis resistance. IL1RAP is minimally expressed in pediatric and adult normal tissues, and human anti-IL1RAP antibodies induce potent antibody-dependent cellular cytotoxicity of EwS cells. Therefore, we define IL1RAP as a new cell surface target in EwS, which is potentially exploitable for immunotherapy.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1690DOI Listing
May 2021

ERG transcription factors have a splicing regulatory function involving RBFOX2 that is altered in the EWS-FLI1 oncogenic fusion.

Nucleic Acids Res 2021 05;49(9):5038-5056

University of Liège, Interdisciplinary Cluster for Applied Genoproteomics (GIGA), Liège, Belgium.

ERG family proteins (ERG, FLI1 and FEV) are a subfamily of ETS transcription factors with key roles in physiology and development. In Ewing sarcoma, the oncogenic fusion protein EWS-FLI1 regulates both transcription and alternative splicing of pre-messenger RNAs. However, whether wild-type ERG family proteins might regulate splicing is unknown. Here, we show that wild-type ERG proteins associate with spliceosomal components, are found on nascent RNAs, and induce alternative splicing when recruited onto a reporter minigene. Transcriptomic analysis revealed that ERG and FLI1 regulate large numbers of alternative spliced exons (ASEs) enriched with RBFOX2 motifs and co-regulated by this splicing factor. ERG and FLI1 are associated with RBFOX2 via their conserved carboxy-terminal domain, which is present in EWS-FLI1. Accordingly, EWS-FLI1 is also associated with RBFOX2 and regulates ASEs enriched in RBFOX2 motifs. However, in contrast to wild-type ERG and FLI1, EWS-FLI1 often antagonizes RBFOX2 effects on exon inclusion. In particular, EWS-FLI1 reduces RBFOX2 binding to the ADD3 pre-mRNA, thus increasing its long isoform, which represses the mesenchymal phenotype of Ewing sarcoma cells. Our findings reveal a RBFOX2-mediated splicing regulatory function of wild-type ERG family proteins, that is altered in EWS-FLI1 and contributes to the Ewing sarcoma cell phenotype.
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http://dx.doi.org/10.1093/nar/gkab305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136815PMC
May 2021

SMARCA4-deficient rhabdoid tumours show intermediate molecular features between SMARCB1-deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type.

J Pathol 2021 May 17. Epub 2021 May 17.

INSERM, U830, Pediatric Translational Research, PSL Research University, Institut Curie, Paris, France.

Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRT ) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRT ) instead of SMARCB1. However, very few ECRT cases have been published to date, and a systematic characterization of ECRT is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRT and show that they are comparable to those of ECRT We also assess whether ECRT , ECRT , and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics-based tumour classification approaches, we demonstrate that ECRT display molecular features intermediate between SCCOHT and ECRT ; however, ECRT appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRT , potentially supporting their continuous separate classification. Lastly, we show that ECRT display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the 'rhabdoid tumour' spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5705DOI Listing
May 2021

STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma.

Cancer Cell 2021 Jun 29;39(6):810-826.e9. Epub 2021 Apr 29.

INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France; Unité de Génétique Somatique, Service d'oncogénétique, Institut Curie, Centre Hospitalier, 75005 Paris, France. Electronic address:

STAG2, a cohesin family gene, is among the most recurrently mutated genes in cancer. STAG2 loss of function (LOF) is associated with aggressive behavior in Ewing sarcoma, a childhood cancer driven by aberrant transcription induced by the EWSR1-FLI1 fusion oncogene. Here, using isogenic Ewing cells, we show that, while STAG2 LOF profoundly changes the transcriptome, it does not significantly impact EWSR1-FLI1, CTCF/cohesin, or acetylated H3K27 DNA binding patterns. In contrast, it strongly alters the anchored dynamic loop extrusion process at boundary CTCF sites and dramatically decreases promoter-enhancer interactions, particularly affecting the expression of genes regulated by EWSR1-FLI1 at GGAA microsatellite neo-enhancers. Down-modulation of cis-mediated EWSR1-FLI1 activity, observed in STAG2-LOF conditions, is associated with enhanced migration and invasion properties of Ewing cells previously observed in EWSR1-FLI1 cells. Our study illuminates a process whereby STAG2-LOF fine-tunes the activity of an oncogenic transcription factor through altered CTCF-anchored loop extrusion and cis-mediated enhancer mechanisms.
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http://dx.doi.org/10.1016/j.ccell.2021.04.001DOI Listing
June 2021

Transfer of distal peroneus longus tendon to tibialis anterior by retrograde fixation to treat spastic equinovarus foot in adults: Surgical Technique and Preliminary Results.

Orthop Traumatol Surg Res 2021 Apr 14:102935. Epub 2021 Apr 14.

Centre Hopitalier Universitaire Necker enfants malades, 149, rue de Sèvres, 75015 Paris, France. Electronic address:

We describe a retrograde transfer of the distal tendon of the peroneus longus (PL) onto the tibialis anterior (TA) tendon to treat spastic equinovarus foot (SEVF) in adults. The fact that the distal tendon insertions of the PL and TA are a mirror image makes them antagonists. The aim is to divert the distal tendon in front the inactive distal PL tendon, by fixing to the TA in the middle third of the lower leg. This transforms it into a dorsiflexor and reinforces its eversion ability. The suture level helps to avoid skin impingement when wearing shoes, and the complications inherent to transosseous fixation. In a preliminary case series of 10 patients, we found no complications at a mean follow-up of 4.7 years. The Foot Posture Index-6 improved by an average of 2.4 points. Four patients had regained active dorsiflexion. All patients reduced their use of orthotics. All patients improved according to Goal Attainment Scaling.
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http://dx.doi.org/10.1016/j.otsr.2021.102935DOI Listing
April 2021

The transcriptional landscape of Shh medulloblastoma.

Nat Commun 2021 03 19;12(1):1749. Epub 2021 Mar 19.

Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
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http://dx.doi.org/10.1038/s41467-021-21883-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979819PMC
March 2021

The epigenetic regulator RINF (CXXC5) maintains SMAD7 expression in human immature erythroid cells and sustains red blood cells expansion.

Haematologica 2020 11 26;Online ahead of print. Epub 2020 Nov 26.

Université de Paris, Institut Cochin, INSERM, CNRS, F-75014 Paris, France; Laboratory of Excellence GR-ex, Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris.

The gene CXXC5, encoding a Retinoid-Inducible Nuclear Factor (RINF), is located within a region at 5q31.2 commonly deleted in myelodysplastic syndrome (MDS) and adult acute myeloid leukemia (AML). RINF may act as an epigenetic regulator and has been proposed as a tumor suppressor in hematopoietic malignancies. However, functional studies in normal hematopoiesis are lacking, and its mechanism of action is unknow. Here, we evaluated the consequences of RINF silencing on cytokineinduced erythroid differentiation of human primary CD34+ progenitors. We found that RINF is expressed in immature erythroid cells and that RINF-knockdown accelerated erythropoietin-driven maturation, leading to a significant reduction (~45%) in the number of red blood cells (RBCs), without affecting cell viability. The phenotype induced by RINF-silencing was TGFβ-dependent and mediated by SMAD7, a TGFβ- signaling inhibitor. RINF upregulates SMAD7 expression by direct binding to its promoter and we found a close correlation between RINF and SMAD7 mRNA levels both in CD34+ cells isolated from bone marrow of healthy donors and MDS patients with del(5q). Importantly, RINF knockdown attenuated SMAD7 expression in primary cells and ectopic SMAD7 expression was sufficient to prevent the RINF knockdowndependent erythroid phenotype. Finally, RINF silencing affects 5’-hydroxymethylation of human erythroblasts, in agreement with its recently described role as a Tet2- anchoring platform in mouse. Altogether, our data bring insight into how the epigenetic factor RINF, as a transcriptional regulator of SMAD7, may fine-tune cell sensitivity to TGFβ superfamily cytokines and thus play an important role in both normal and pathological erythropoiesis.
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http://dx.doi.org/10.3324/haematol.2020.263558DOI Listing
November 2020

Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity.

Nat Commun 2020 09 15;11(1):4629. Epub 2020 Sep 15.

University Children's Hospital, Department of Oncology and Children's Research Center, Steinwiesstrasse 75, CH-8032, Zurich, Switzerland.

Cancer therapy is currently shifting from broadly used cytotoxic drugs to patient-specific precision therapies. Druggable driver oncogenes, identified by molecular analyses, are present in only a subset of patients. Functional profiling of primary tumor cells could circumvent these limitations, but suitable platforms are unavailable for most cancer entities. Here, we describe an in vitro drug profiling platform for rhabdomyosarcoma (RMS), using a living biobank composed of twenty RMS patient-derived xenografts (PDX) for high-throughput drug testing. Optimized in vitro conditions preserve phenotypic and molecular characteristics of primary PDX cells and are compatible with propagation of cells directly isolated from patient tumors. Besides a heterogeneous spectrum of responses of largely patient-specific vulnerabilities, profiling with a large drug library reveals a strong sensitivity towards AKT inhibitors in a subgroup of RMS. Overall, our study highlights the feasibility of in vitro drug profiling of primary RMS for patient-specific treatment selection in a co-clinical setting.
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http://dx.doi.org/10.1038/s41467-020-18388-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492191PMC
September 2020

Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable -Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group.

J Clin Oncol 2020 11 9;38(31):3685-3697. Epub 2020 Sep 9.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: For localized, resectable neuroblastoma without amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome.

Patients And Methods: Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children's Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group.

Results: Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, = .038).

Conclusion: Genomic aberrations of resectable non-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.
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http://dx.doi.org/10.1200/JCO.18.02132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605396PMC
November 2020

Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.

PLoS One 2020 3;15(9):e0237792. Epub 2020 Sep 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America.

Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor.

Methods: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry).

Results: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8).

Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.

Impact: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237792PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470401PMC
October 2020

Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.

Nat Med 2020 05 27;26(5):712-719. Epub 2020 Apr 27.

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. ), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.
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http://dx.doi.org/10.1038/s41591-020-0821-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992505PMC
May 2020

High CD44 expression is not a prognosis marker in patients with high-risk neuroblastoma.

EBioMedicine 2020 03 19;53:102702. Epub 2020 Mar 19.

Inserm U830, Institut Curie, PSL Research University, Equipe Labellisée Ligue contre le Cancer, Paris F-75005, France. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2020.102702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083781PMC
March 2020

High Specificity of BCL11B and GLG1 for EWSR1-FLI1 and EWSR1-ERG Positive Ewing Sarcoma.

Cancers (Basel) 2020 Mar 10;12(3). Epub 2020 Mar 10.

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, 80337 Munich, Germany.

Ewing sarcoma (EwS) is an aggressive cancer displaying an undifferentiated small-round-cell histomorphology that can be easily confused with a broad spectrum of differential diagnoses. Using comparative transcriptomics and immunohistochemistry (IHC), we previously identified BCL11B and GLG1 as potential specific auxiliary IHC markers for -positive EwS. Herein, we aimed at validating the specificity of both markers in a far larger and independent cohort of EwS (including -positive cases) and differential diagnoses. Furthermore, we evaluated their intra-tumoral expression heterogeneity. Thus, we stained tissue microarrays from 133 molecularly confirmed EwS cases and 320 samples from morphological mimics, as well as a series of patient-derived xenograft (PDX) models for BCL11B, GLG1, and CD99, and systematically assessed the immunoreactivity and optimal cut-offs for each marker. These analyses demonstrated that high BCL11B and/or GLG1 immunoreactivity in CD99-positive cases had a specificity of 97.5% and an accuracy of 87.4% for diagnosing EwS solely by IHC, and that the markers were expressed by -positive EwS. Only little intra-tumoral heterogeneity in immunoreactivity was observed for differential diagnoses. These results indicate that BCL11B and GLG1 may help as specific auxiliary IHC markers in diagnosing EwS in conjunction with CD99, especially if confirmatory molecular diagnostics are not available.
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http://dx.doi.org/10.3390/cancers12030644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139395PMC
March 2020

Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution.

Cell Rep 2020 02;30(6):1767-1779.e6

INSERM U900, 75005 Paris, France; Mines ParisTech, PSL Research University, CBIO-Centre for Computational Biology, 75006 Paris, France; Institut Curie, PSL Research University, 75005 Paris, France. Electronic address:

EWSR1-FLI1, the chimeric oncogene specific for Ewing sarcoma (EwS), induces a cascade of signaling events leading to cell transformation. However, it remains elusive how genetically homogeneous EwS cells can drive the heterogeneity of transcriptional programs. Here, we combine independent component analysis of single-cell RNA sequencing data from diverse cell types and model systems with time-resolved mapping of EWSR1-FLI1 binding sites and of open chromatin regions to characterize dynamic cellular processes associated with EWSR1-FLI1 activity. We thus define an exquisitely specific and direct enhancer-driven EWSR1-FLI1 program. In EwS tumors, cell proliferation and strong oxidative phosphorylation metabolism are associated with a well-defined range of EWSR1-FLI1 activity. In contrast, a subpopulation of cells from below and above the intermediary EWSR1-FLI1 activity is characterized by increased hypoxia. Overall, our study reveals sources of intratumoral heterogeneity within EwS tumors.
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http://dx.doi.org/10.1016/j.celrep.2020.01.049DOI Listing
February 2020

ZRANB2 and SYF2-mediated splicing programs converging on ECT2 are involved in breast cancer cell resistance to doxorubicin.

Nucleic Acids Res 2020 03;48(5):2676-2693

Institut Curie, PSL Research University, CNRS UMR 3348, F-91405 Orsay, France.

Besides analyses of specific alternative splicing (AS) variants, little is known about AS regulatory pathways and programs involved in anticancer drug resistance. Doxorubicin is widely used in breast cancer chemotherapy. Here, we identified 1723 AS events and 41 splicing factors regulated in a breast cancer cell model of acquired resistance to doxorubicin. An RNAi screen on splicing factors identified the little studied ZRANB2 and SYF2, whose depletion partially reversed doxorubicin resistance. By RNAi and RNA-seq in resistant cells, we found that the AS programs controlled by ZRANB2 and SYF2 were enriched in resistance-associated AS events, and converged on the ECT2 splice variant including exon 5 (ECT2-Ex5+). Both ZRANB2 and SYF2 were found associated with ECT2 pre-messenger RNA, and ECT2-Ex5+ isoform depletion reduced doxorubicin resistance. Following doxorubicin treatment, resistant cells accumulated in S phase, which partially depended on ZRANB2, SYF2 and the ECT2-Ex5+ isoform. Finally, doxorubicin combination with an oligonucleotide inhibiting ECT2-Ex5 inclusion reduced doxorubicin-resistant tumor growth in mouse xenografts, and high ECT2-Ex5 inclusion levels were associated with bad prognosis in breast cancer treated with chemotherapy. Altogether, our data identify AS programs controlled by ZRANB2 and SYF2 and converging on ECT2, that participate to breast cancer cell resistance to doxorubicin.
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http://dx.doi.org/10.1093/nar/gkz1213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049692PMC
March 2020

Association of Partial Chromosome 3 Deletion in Uveal Melanomas With Metastasis-Free Survival.

JAMA Ophthalmol 2020 02;138(2):182-188

Department of Genetics, Institut Curie, PSL Research University, Paris, France.

Importance: Studies on uveal melanomas (UMs) have demonstrated the prognostic value of 8q gain and monosomy 3, but the prognosis of UMs with partial deletion of chromosome 3 remains to be defined.

Objective: To examine the association of partial chromosome 3 deletion in UMs with metastasis-free survival.

Design, Setting, And Participants: This retrospective cohort study of 1088 consecutive comparative genomic hybridization arrays performed from May 1, 2006, to July 31, 2015, assessed patients presenting with UMs with and without partial loss of chromosome 3 at a referral center. Data analysis was performed from September 1, 2017, to November 30, 2017.

Exposure: Uveal melanoma with or without partial loss of chromosome 3.

Main Outcomes And Measures: Metastasis-free survival and overall survival at 60 months.

Results: Of the 1088 consecutive comparative genomic hybridization arrays that were performed, 43 UMs (4.0%) in 43 patients (median age, 58 years [range, 12-79 years]; 22 [51%] female) carried partial deletions of chromosome 3. Median follow-up was 66 months (range, 1.2-126.2 months). Metastasis-free survival at 60 months was 33.6% (95% CI, 15.8%-71.4%) for UMs that carried a deletion of the BAP1 (BRCA1 associated protein 1) locus (BAP1del; 24 tumors) and 80.5% (95% CI, 64.8%-100%) for UMs without the loss of the BAP1 locus (BAP1 normal [BAP1nl]; 19 tumors) (log-rank P = .001). Overall survival at 60 months was 64.5% (95% CI, 43.5%-95.8%) in the BAP1del group vs 84.1% (95% CI, 69.0%-100%) in the BAP1nl group (log-rank P < .001). In these 43 cases, metastasis-free survival at 60 months was 100% for UMs without loss of the BAP1 locus or 8q gain, 70.0% (95% CI, 50.5%-96.9%) for UMs that carried 1 of these alterations, and 12.5% (95% CI, 2.1%-73.7%) for those that carried both (log-rank P < .001). Similarly, overall survival at 60 months was 100% for UMs without loss of the BAP1 locus or 8q gain, 80.8% (95% CI, 63.3%-100%) for UMs that carried 1 of these alterations, and 46.7% (95% CI, 23.3%-93.6%) for those that carried both (log-rank P < .001).

Conclusions And Relevance: These findings suggest that partial deletion of chromosome 3 encompassing the BAP1 locus is associated with poor prognosis. A cytogenetic classification of UMs could be proposed based on the status of the BAP1 locus instead of the chromosome 3 locus, while also taking chromosome 8q into account.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.5403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990836PMC
February 2020

Aurora A Kinase Inhibition Destabilizes PAX3-FOXO1 and MYCN and Synergizes with Navitoclax to Induce Rhabdomyosarcoma Cell Death.

Cancer Res 2020 02 30;80(4):832-842. Epub 2019 Dec 30.

Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.

The clinically aggressive alveolar rhabdomyosarcoma (RMS) subtype is characterized by expression of the oncogenic fusion protein PAX3-FOXO1, which is critical for tumorigenesis and cell survival. Here, we studied the mechanism of cell death induced by loss of PAX3-FOXO1 expression and identified a novel pharmacologic combination therapy that interferes with PAX3-FOXO1 biology at different levels. Depletion of PAX3-FOXO1 in fusion-positive (FP)-RMS cells induced intrinsic apoptosis in a NOXA-dependent manner. This was pharmacologically mimicked by the BH3 mimetic navitoclax, identified as top compound in a screen from 208 targeted compounds. In a parallel approach, and to identify drugs that alter the stability of PAX3-FOXO1 protein, the same drug library was screened and fusion protein levels were directly measured as a read-out. This revealed that inhibition of Aurora kinase A most efficiently negatively affected PAX3-FOXO1 protein levels. Interestingly, this occurred through a novel specific phosphorylation event in and binding to the fusion protein. Aurora kinase A inhibition also destabilized MYCN, which is both a functionally important oncogene and transcriptional target of PAX3-FOXO1. Combined treatment with an Aurora kinase A inhibitor and navitoclax in FP-RMS cell lines and patient-derived xenografts synergistically induced cell death and significantly slowed tumor growth. These studies identify a novel functional interaction of Aurora kinase A with both PAX3-FOXO1 and its effector MYCN, and reveal new opportunities for targeted combination treatment of FP-RMS. SIGNIFICANCE: These findings show that Aurora kinase A and Bcl-2 family proteins are potential targets for FP-RMS.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1479DOI Listing
February 2020

Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors.

Cancer Cell 2019 12 7;36(6):597-612.e8. Epub 2019 Nov 7.

PSL Research University, Institut Curie Research Center, INSERM U830, Paris, France; PSL Research University, Institut Curie Research Center, Translational Research Department, Paris, France. Electronic address:

Rhabdoid tumors (RTs) are genomically simple pediatric cancers driven by the biallelic inactivation of SMARCB1, leading to SWI/SNF chromatin remodeler complex deficiency. Comprehensive evaluation of the immune infiltrates of human and mice RTs, including immunohistochemistry, bulk RNA sequencing and DNA methylation profiling studies showed a high rate of tumors infiltrated by T and myeloid cells. Single-cell RNA (scRNA) and T cell receptor sequencing highlighted the heterogeneity of these cells and revealed therapeutically targetable exhausted effector and clonally expanded tissue resident memory CD8 T subpopulations, likely representing tumor-specific cells. Checkpoint blockade therapy in an experimental RT model induced the regression of established tumors and durable immune responses. Finally, we show that one mechanism mediating RTs immunogenicity involves SMARCB1-dependent re-expression of endogenous retroviruses and interferon-signaling activation.
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http://dx.doi.org/10.1016/j.ccell.2019.10.008DOI Listing
December 2019

Class I HDAC inhibitors enhance YB-1 acetylation and oxidative stress to block sarcoma metastasis.

EMBO Rep 2019 12 31;20(12):e48375. Epub 2019 Oct 31.

Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.

Outcomes for metastatic Ewing sarcoma and osteosarcoma are dismal and have not changed for decades. Oxidative stress attenuates melanoma metastasis, and melanoma cells must reduce oxidative stress to metastasize. We explored this in sarcomas by screening for oxidative stress sensitizers, which identified the class I HDAC inhibitor MS-275 as enhancing vulnerability to reactive oxygen species (ROS) in sarcoma cells. Mechanistically, MS-275 inhibits YB-1 deacetylation, decreasing its binding to 5'-UTRs of NFE2L2 encoding the antioxidant factor NRF2, thereby reducing NFE2L2 translation and synthesis of NRF2 to increase cellular ROS. By global acetylomics, MS-275 promotes rapid acetylation of the YB-1 RNA-binding protein at lysine-81, blocking binding and translational activation of NFE2L2, as well as known YB-1 mRNA targets, HIF1A, and the stress granule nucleator, G3BP1. MS-275 dramatically reduces sarcoma metastasis in vivo, but an MS-275-resistant YB-1K81-to-alanine mutant restores metastatic capacity and NRF2, HIF1α, and G3BP1 synthesis in MS-275-treated mice. These studies describe a novel function for MS-275 through enhanced YB-1 acetylation, thus inhibiting YB-1 translational control of key cytoprotective factors and its pro-metastatic activity.
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http://dx.doi.org/10.15252/embr.201948375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893361PMC
December 2019

ETS Proteins Bind with Glucocorticoid Receptors: Relevance for Treatment of Ewing Sarcoma.

Cell Rep 2019 10;29(1):104-117.e4

Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

The glucocorticoid receptor (GR) acts as a ubiquitous cortisol-dependent transcription factor (TF). To identify co-factors, we used protein-fragment complementation assays and found that GR recognizes FLI1 and additional ETS family proteins, TFs relaying proliferation and/or migration signals. Following steroid-dependent translocation of FLI1 and GR to the nucleus, the FLI1-specific domain (FLS) binds with GR and strongly enhances GR's transcriptional activity. This interaction has functional consequences in Ewing sarcoma (ES), childhood and adolescence bone malignancies driven by fusions between EWSR1 and FLI1. In vitro, GR knockdown inhibited the migration and proliferation of ES cells, and in animal models, antagonizing GR (or lowering cortisol) retarded both tumor growth and metastasis from bone to lung. Taken together, our findings offer mechanistic rationale for repurposing GR-targeting drugs for the treatment of patients with ES.
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http://dx.doi.org/10.1016/j.celrep.2019.08.088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899513PMC
October 2019

Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes.

Nat Commun 2019 09 11;10(1):4128. Epub 2019 Sep 11.

INSERM U830, Équipe Labellisée LNCC Genetics and Biology of Pediatric Cancers, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, Paris, France.

Pediatric malignancies including Ewing sarcoma (EwS) feature a paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome. Here, we demonstrate in EwS how cooperation of dominant oncogenes and regulatory germline variants determine tumor growth, patient survival and drug response. Binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls expression of the transcription factor MYBL2 mediating these phenotypes. Whole-genome and RNA sequencing reveals that variability at this locus is inherited via the germline and is associated with variable inter-tumoral MYBL2 expression. High MYBL2 levels sensitize EwS cells for inhibition of its upstream activating kinase CDK2 in vitro and in vivo, suggesting MYBL2 as a putative biomarker for anti-CDK2-therapy. Collectively, we establish cooperation of somatic mutations and regulatory germline variants as a major determinant of tumor progression and highlight the importance of integrating the regulatory genome in precision medicine.
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http://dx.doi.org/10.1038/s41467-019-12071-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739408PMC
September 2019

ALK mutation dynamics and clonal evolution in a neuroblastoma model exhibiting two ALK mutations.

Oncotarget 2019 Aug 13;10(48):4937-4950. Epub 2019 Aug 13.

Institut Curie, PSL Research University, Inserm U830, Equipe Labellisée Ligue contre le Cancer, Paris F-75005, France.

The gene is a major oncogene of neuroblastoma cases exhibiting ALK activating mutations. Here, we characterized two neuroblastoma cell lines established from a stage 4 patient at diagnosis either from the primary tumor (PT) or from the bone marrow (BM). Both cell lines exhibited similar genomic profiles. All cells in the BM-derived cell line exhibited an ALK F1174L mutation, whereas this mutation was present in only 5% of the cells in the earliest passages of the PT-derived cell line. The BM-derived cell line presented with a higher proliferation rate and injections in Nude mice resulted in tumor formation only for the BM-derived cell line. Next, we observed that the F1174L mutation frequency in the PT-derived cell line increased with successive passages. Further Whole Exome Sequencing revealed a second ALK mutation, L1196M, in this cell line. Digital droplet PCR documented that the allele fractions of both mutations changed upon passages, and that the F1174L mutation reached 50% in late passages, indicating clonal evolution. treatment of the PT-derived cell line exhibiting the F1174L and L1196M mutations with the alectinib inhibitor resulted in an enrichment of the L1196M mutation. Using xenografts, we documented a better efficacy of alectinib compared to crizotinib on tumor growth and an enrichment of the L1196M mutation at the end of both treatments. Finally, single-cell RNA-seq analysis was consistent with both mutations resulting in ALK activation. Altogether, this study provides novel insights into ALK mutation dynamics in a neuroblastoma model harbouring two ALK mutations.
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http://dx.doi.org/10.18632/oncotarget.27119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697636PMC
August 2019

STAG Mutations in Cancer.

Trends Cancer 2019 08 31;5(8):506-520. Epub 2019 Jul 31.

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU, Munich, Germany; Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany; German Cancer Consortium (DKTK), partner site Munich, Munich, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Stromal Antigen 1 and 2 (STAG1/2) are key subunits of the cohesin complex that mediate sister chromatid cohesion, DNA repair, transcriptional regulation, and genome topology. Genetic alterations comprising any of the 11 cohesin-associated genes possibly occur in up to 26% of patients included in The Cancer Genome Atlas (TCGA) studies. STAG2 shows the highest number of putative driver truncating mutations. We provide a comprehensive review of the function of STAG1/2 in human physiology and disease and an integrative analysis of available omics data on STAG alterations in a wide array of cancers, comprising 53 691 patients and 1067 cell lines. Lastly, we discuss opportunities for therapeutic intervention.
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http://dx.doi.org/10.1016/j.trecan.2019.07.001DOI Listing
August 2019

An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma.

EMBO Mol Med 2019 08 22;11(8):e9830. Epub 2019 Jul 22.

Institut Curie, Orsay, France.

Medulloblastoma (MB) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGFβ/Activin pathway occur at very low frequency in Group 3 MB. However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB-PDX. Our data demonstrate that the TGFβ/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.
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http://dx.doi.org/10.15252/emmm.201809830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685082PMC
August 2019
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