المؤلفون: Sturtzel, C, Grissenberger, S, Bozatzi, P, Scheuringer, E, Wenninger-Weinzierl, A, Zajec, Z, Dernovšek, J, Pascoal, S, Gehl, V, Kutsch, A, Granig, A, Rifatbegovic, F, Carre, M, Lang, A, Valtingojer, I, Moll, J, Lötsch, D, Erhart, F, Widhalm, G, Surdez, D, Delattre, O, André, N, Stampfl, J, Tomašič, T, Taschner-Mandl, S, Distel, M

المصدر: Sturtzel, C; Grissenberger, S; Bozatzi, P; Scheuringer, E; Wenninger-Weinzierl, A; Zajec, Z; Dernovšek, J; Pascoal, S; Gehl, V; Kutsch, A; Granig, A; Rifatbegovic, F; Carre, M; Lang, A; Valtingojer, I; Moll, J; Lötsch, D; Erhart, F; Widhalm, G; Surdez, D; Delattre, O; André, N; Stampfl, J; Tomašič, T; Taschner-Mandl, S; Distel, M (2023). Refined high-content imaging-based phenotypic drug screening in zebrafish xenografts. NPJ precision oncology, 7(1):44.

مصطلحات موضوعية: Balgrist University Hospital, Swiss Spinal Cord Injury Center, 610 Medicine & health

الوصف: Zebrafish xenotransplantation models are increasingly applied for phenotypic drug screening to identify small compounds for precision oncology. Larval zebrafish xenografts offer the opportunity to perform drug screens at high-throughput in a complex in vivo environment. However, the full potential of the larval zebrafish xenograft model has not yet been realized and several steps of the drug screening workflow still await automation to increase throughput. Here, we present a robust workflow for drug screening in zebrafish xenografts using high-content imaging. We established embedding methods for high-content imaging of xenografts in 96-well format over consecutive days. In addition, we provide strategies for automated imaging and analysis of zebrafish xenografts including automated tumor cell detection and tumor size analysis over time. We also compared commonly used injection sites and cell labeling dyes and show specific site requirements for tumor cells from different entities. We demonstrate that our setup allows us to investigate proliferation and response to small compounds in several zebrafish xenografts ranging from pediatric sarcomas and neuroblastoma to glioblastoma and leukemia. This fast and cost-efficient assay enables the quantification of anti-tumor efficacy of small compounds in large cohorts of a vertebrate model system in vivo. Our assay may aid in prioritizing compounds or compound combinations for further preclinical and clinical investigations.

وصف الملف: application/pdf

العلاقة: https://www.zora.uzh.ch/id/eprint/235494/1/2023_Sturtzel_Refined_high_content_imaging_based_phenotypic_drug_screening_in_zebrafish_xenografts_NPJPO.pdfTest; info:pmid/37202469; urn:issn:2397-768X

الإتاحة: https://doi.org/10.5167/uzh-23549410.1038/s41698-023-00386-9Test
https://www.zora.uzh.ch/id/eprint/235494Test/
https://www.zora.uzh.ch/id/eprint/235494/1/2023_Sturtzel_Refined_high_content_imaging_based_phenotypic_drug_screening_in_zebrafish_xenografts_NPJPO.pdfTest

المؤلفون: Danielli, S.G., Porpiglia, E., De Micheli, A.J., Navarro, N., Zellinger, M.J., Bechtold, I., Kisele, S., Volken, L., Marques, J.G., Kasper, S., Bode, P.K., Henssen, A.G., Gürgen, D., Delattre, O., Surdez, D., Roma, J., Bühlmann, P., Blau, H.M., Wachtel, M., Schäfer, B.W.

مصطلحات موضوعية: Cancer Research

الوصف: Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest remain elusive. Here, we combined single-cell RNA sequencing, mass cytometry, and high-content imaging to resolve intratumoral heterogeneity of patient-derived primary RMS cultures. We show that the aggressive alveolar RMS (aRMS) subtype contains plastic muscle stem-like cells and cycling progenitors that drive tumor growth, and a subpopulation of differentiated cells that lost its proliferative potential and correlates with better outcomes. While chemotherapy eliminates cycling progenitors, it enriches aRMS for muscle stem-like cells. We screened for drugs hijacking aRMS toward clinically favorable subpopulations and identified a combination of RAF and MEK inhibitors that potently induces myogenic differentiation and inhibits tumor growth. Overall, our work provides insights into the developmental states underlying aRMS aggressiveness, chemoresistance, and progression and identifies the RAS pathway as a promising therapeutic target.

وصف الملف: application/pdf; other

العلاقة: http://edoc.mdc-berlin.de/23121/1/23121oa.pdfTest; http://edoc.mdc-berlin.de/23121/6/23121suppl.zipTest; Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with therapeutic relevance. Danielli, S.G. and Porpiglia, E. and De Micheli, A.J. and Navarro, N. and Zellinger, M.J. and Bechtold, I. and Kisele, S. and Volken, L. and Marques, J.G. and Kasper, S. and Bode, P.K. and Henssen, A.G. and Gürgen, D. and Delattre, O. and Surdez, D. and Roma, J. and Bühlmann, P. and Blau, H.M. and Wachtel, M. and Schäfer, B.W. Science Advances 9 (6): eade9238. 10 February 2023

الإتاحة: https://doi.org/10.1126/sciadv.ade9238Test
http://edoc.mdc-berlin.de/23121Test/
https://edoc.mdc-berlin.de/23121Test/
http://edoc.mdc-berlin.de/23121/1/23121oa.pdfTest
http://edoc.mdc-berlin.de/23121/6/23121suppl.zipTest

المؤلفون: Tucker, ER, Jiménez, I, Chen, L, Bellini, A, Gorrini, C, Calton, E, Gao, Q, Che, H, Poon, E, Jamin, Y, Martins Da Costa, B, Barker, K, Shrestha, S, Hutchinson, JC, Dhariwal, S, Goodman, A, Del Nery, E, Gestraud, P, Bhalshankar, J, Iddir, Y, Saberi-Ansari, E, Saint-Charles, A, Geoerger, B, Marques Da Costa, ME, Pierre-Eugène, C, Janoueix-Lerosey, I, Decaudin, D, Nemati, F, Carcaboso, AM, Surdez, D, Delattre, O, George, SL, Chesler, L, Tweddle, DA, Schleiermacher, G

المساهمون: Gorrini, Chiara, Gao, Qiong, Poon, Evon, Shrestha, Sumana, George, Sally, Chesler, Louis

جغرافية الموضوع: United States

الوصف: PURPOSE: ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1%-2% of cases. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single-agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data have suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. EXPERIMENTAL DESIGN: We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin, and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient-derived xenografts (PDX). RESULTS: Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX, lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth. CONCLUSIONS: In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.

وصف الملف: Print-Electronic; CCR-22-2274 -; application/pdf

العلاقة: 712745; Clinical Cancer Research, 2023, pp. CCR-22-2274 -; https://repository.icr.ac.uk/handle/internal/5729Test

الإتاحة: https://doi.org/10.1158/1078-0432.CCR-22-2274Test
https://repository.icr.ac.uk/handle/internal/5729Test

المؤلفون: Sturtzel, C., Grissenberger, S., Bozatzi, P., Scheuringer, E., Wenninger-Weinzierl, A., Zajec, Z., Dernovšek, J., Pascoal, S., Gehl, V., Kutsch, A., Granig, A., Rifatbegovic, F., Carre, M., Lang, A., Valtingojer, I., Moll, J., Lötsch, D., Erhart, F., Widhalm, G., Surdez, D., Delattre, O., André, N., Stampfl, J., Tomašič, T., Taschner-Mandl, S., Distel, M.

المساهمون: Österreichische Forschungsförderungsgesellschaft, OeAD-GmbH, Österreichischen Akademie der Wissenschaften, Comprehensive Cancer Center Forschungsförderung der Initiative Krebsforschung, MedUni Wien, Vienna Science and Technology Fund, EC | Horizon 2020 Framework Programme, Javna Agencija za Raziskovalno Dejavnost RS, Sanofi

المصدر: npj Precision Oncology ; volume 7, issue 1 ; ISSN 2397-768X

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Zebrafish xenotransplantation models are increasingly applied for phenotypic drug screening to identify small compounds for precision oncology. Larval zebrafish xenografts offer the opportunity to perform drug screens at high-throughput in a complex in vivo environment. However, the full potential of the larval zebrafish xenograft model has not yet been realized and several steps of the drug screening workflow still await automation to increase throughput. Here, we present a robust workflow for drug screening in zebrafish xenografts using high-content imaging. We established embedding methods for high-content imaging of xenografts in 96-well format over consecutive days. In addition, we provide strategies for automated imaging and analysis of zebrafish xenografts including automated tumor cell detection and tumor size analysis over time. We also compared commonly used injection sites and cell labeling dyes and show specific site requirements for tumor cells from different entities. We demonstrate that our setup allows us to investigate proliferation and response to small compounds in several zebrafish xenografts ranging from pediatric sarcomas and neuroblastoma to glioblastoma and leukemia. This fast and cost-efficient assay enables the quantification of anti-tumor efficacy of small compounds in large cohorts of a vertebrate model system in vivo. Our assay may aid in prioritizing compounds or compound combinations for further preclinical and clinical investigations.

الإتاحة: https://doi.org/10.1038/s41698-023-00386-9Test
https://www.nature.com/articles/s41698-023-00386-9.pdfTest
https://www.nature.com/articles/s41698-023-00386-9Test

المؤلفون: Guinot, A., Tabone-Eglinger, S., Isnardi, V., Bahri, H., Surdez, D., Delattre, O., Pierron, G., Villemeur, M., Lapouble, E., Brahmi, M., Bouhamama, A., Corradini, N., Marec-Bérard, Perrine

المصدر: European Journal of Cancer ; volume 179, page 56-64 ; ISSN 0959-8049

مصطلحات موضوعية: Cancer Research, Oncology

الإتاحة: https://doi.org/10.1016/j.ejca.2022.11.002Test
https://api.elsevier.com/content/article/PII:S0959804922013375?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0959804922013375?httpAccept=text/plainTest

المؤلفون: Ruhen, O, Lak, NSM, Stutterheim, J, Danielli, SG, Chicard, M, Iddir, Y, Saint-Charles, A, Di Paolo, V, Tombolan, L, Gatz, SA, Aladowicz, E, Proszek, P, Jamal, S, Stankunaite, R, Hughes, D, Carter, P, Izquierdo, E, Wasti, A, Chisholm, JC, George, SL, Pace, E, Chesler, L, Aerts, I, Pierron, G, Zaidi, S, Delattre, O, Surdez, D, Kelsey, A, Hubank, M, Bonvini, P, Bisogno, G, Di Giannatale, A, Schleiermacher, G, Schäfer, BW, Tytgat, GAM, Shipley, J

المساهمون: Stankunaite, Reda, Wasti, Ajla, George, Sally, Chesler, Louis, Shipley, Janet

مصطلحات موضوعية: Humans, Child, Mice, Animals, Circulating Tumor DNA, Feasibility Studies, Prospective Studies, Biomarkers, Tumor, Mutation, Neoplasms, Rhabdomyosarcoma, Embryonal

جغرافية الموضوع: United States

الوصف: PURPOSE: Rhabdomyosarcomas (RMS) are rare neoplasms affecting children and young adults. Efforts to improve patient survival have been undermined by a lack of suitable disease markers. Plasma circulating tumor DNA (ctDNA) has shown promise as a potential minimally invasive biomarker and monitoring tool in other cancers; however, it remains underexplored in RMS. We aimed to determine the feasibility of identifying and quantifying ctDNA in plasma as a marker of disease burden and/or treatment response using blood samples from RMS mouse models and patients. METHODS: We established mouse models of RMS and applied quantitative polymerase chain reaction (PCR) and droplet digital PCR (ddPCR) to detect ctDNA within the mouse plasma. Potential driver mutations, copy-number alterations, and DNA breakpoints associated with PAX3/7-FOXO1 gene fusions were identified in the RMS samples collected at diagnosis. Patient-matched plasma samples collected from 28 patients with RMS before, during, and after treatment were analyzed for the presence of ctDNA via ddPCR, panel sequencing, and/or whole-exome sequencing. RESULTS: Human tumor-derived DNA was detectable in plasma samples from mouse models of RMS and correlated with tumor burden. In patients, ctDNA was detected in 14/18 pretreatment plasma samples with ddPCR and 7/7 cases assessed by sequencing. Levels of ctDNA at diagnosis were significantly higher in patients with unfavorable tumor sites, positive nodal status, and metastasis. In patients with serial plasma samples (n = 18), fluctuations in ctDNA levels corresponded to treatment response. CONCLUSION: Comprehensive ctDNA analysis combining high sensitivity and throughput can identify key molecular drivers in RMS models and patients, suggesting potential as a minimally invasive biomarker. Preclinical assessment of treatments using mouse models and further patient testing through prospective clinical trials are now warranted.

وصف الملف: Print; application/pdf

العلاقة: JCO Precision Oncology, 2022, 6 (6), pp. e2100534 -; https://repository.icr.ac.uk/handle/internal/5614Test

الإتاحة: https://doi.org/10.1200/PO.21.00534Test
https://repository.icr.ac.uk/handle/internal/5614Test

المؤلفون: Surdez, D., Zaidi, S., Grossetete, S., Laud-Duval, Sole Ferre, A., Mous, L., Vourc'h, T., Tirode, F., Pierron, G., Raynal, V., Baulande, S., Brunet, E., Hill, V., Delattre, O.

المصدر: Cancer Cell

الوصف: 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-FLI1low 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.

العلاقة: info:eu-repo/grantAgreement/EC/H2020/826121/; https://zenodo.org/communities/ipcTest; https://zenodo.org/record/4748666Test; https://doi.org/10.1016/j.ccell.2021.04.001Test; oai:zenodo.org:4748666

الإتاحة: https://doi.org/10.1016/j.ccell.2021.04.001Test
https://zenodo.org/record/4748666Test

المؤلفون: Peneder, P, Stutz, AM, Surdez, D, Krumbholz, M, Semper, S, Chicard, M, Sheffield, NC, Pierron, G, Lapouble, E, Totzl, M, Erguner, B, Barreca, D, Rendeiro, AF, Agaimy, A, Boztug, H, Engstler, G, Dworzak, M, Bernkopf, M, Taschner-Mandl, S, Ambros, IM, Myklebost, O, Marec-Berard, P, Burchill, SA, Brennan, B, Strauss, SJ, Whelan, J, Schleiermacher, G, Schaefer, C, Dirksen, U, Hutter, C, Boye, K, Ambros, PF, Delattre, O, Metzler, M, Bock, C, Tomazou, EM

المصدر: Nature Communications , 12 (1) , Article 3230. (2021)

مصطلحات موضوعية: Biomarkers, Cancer genomics, Epigenomics, Paediatric cancer, Software

الوصف: 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.

وصف الملف: text

العلاقة: https://discovery.ucl.ac.uk/id/eprint/10131280/1/Strauss_Multimodal%20analysis%20of%20cell-free%20DNA%20whole-genome%20sequencing%20for%20pediatric%20cancers%20with%20low%20mutational%20burden_VoR.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10131280Test/

الإتاحة: https://discovery.ucl.ac.uk/id/eprint/10131280/1/Strauss_Multimodal%20analysis%20of%20cell-free%20DNA%20whole-genome%20sequencing%20for%20pediatric%20cancers%20with%20low%20mutational%20burden_VoR.pdfTest
https://discovery.ucl.ac.uk/id/eprint/10131280Test/

المؤلفون: Saulnier, O, Guedri-Idjouadiene, K, Aynaud, M-M, Chakraborty, A, Bruyr, J, Pineau, J, O'Grady, T, Mirabeau, O, Grossetete, S, Galvan, B, Claes, M, Hassoun, ZAO, Sadacca, B, Laud, K, Zaidi, S, Surdez, D, Baulande, S, Rambout, X, Tirode, F, Dutertre, M, Delattre, O, Dequiedt, F

وصف الملف: 5038 - 5056

العلاقة: NUCLEIC ACIDS RESEARCH; https://qmro.qmul.ac.uk/xmlui/handle/123456789/77751Test

الإتاحة: https://doi.org/10.1093/nar/gkab305Test
https://qmro.qmul.ac.uk/xmlui/handle/123456789/77751Test

المؤلفون: Srivastava S., Nataraj N. B., Sekar A., Ghosh S., Bornstein C., Drago-Garcia D., Roth L., Romaniello D., Marrocco I., David E., Gilad Y., Lauriola M., Rotkopf R., Kimchi A., Haga Y., Tsutsumi Y., Mirabeau O., Surdez D., Zinovyev A., Delattre O., Kovar H., Amit I., Yarden Y.

المساهمون: Srivastava S., Nataraj N.B., Sekar A., Ghosh S., Bornstein C., Drago-Garcia D., Roth L., Romaniello D., Marrocco I., David E., Gilad Y., Lauriola M., Rotkopf R., Kimchi A., Haga Y., Tsutsumi Y., Mirabeau O., Surdez D., Zinovyev A., Delattre O., Kovar H., Amit I., Yarden Y.

مصطلحات موضوعية: cancer therapy, Ewing sarcoma, glucocorticoid receptor, metastasi, protein-fragment complementation assay

الوصف: 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.

وصف الملف: STAMPA

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/31577941; info:eu-repo/semantics/altIdentifier/wos/WOS:000488614600009; volume:29; issue:1; firstpage:104; lastpage:117; numberofpages:14; journal:CELL REPORTS; http://hdl.handle.net/11585/714523Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85072272041; http://www.sciencedirect.com/science/journal/22111247Test

الإتاحة: https://doi.org/10.1016/j.celrep.2019.08.088Test
http://hdl.handle.net/11585/714523Test
http://www.sciencedirect.com/science/journal/22111247Test