Sabine Taschner-Mandl Group
Neuroblastoma is the most common extracranial solid pediatric cancer accounting for 8-10% of cancers in childhood and 15% of pediatric oncology deaths. Neuroblastoma arises from the developing sympatho-adrenal lineage during the embryonic development. It is a genetically heterogeneous disease with a diverse clinical outcome ranging from spontaneous tumour regression to malignant metastatic disease with relapses and poor response to current therapy. While patients whose tumours undergo spontaneous regression or maturation (ganglioneuroblastomas, ganglioneuromas) have mostly an excellent outcome, only a minority of children with aggressive tumours can be cured. Despite the advances in genomic and trancriptomic analyses, the identification of molecular determinants of the very poor therapeutic response and worst outcome of high-risk patients remains challenging. Thus, a better understanding of the biology of both, spontaneously regressing/maturing and aggressive tumours is of high interest to develop novel treatment approaches.
Biology of high-risk neuroblastoma
One of our main research interests is the biology of high-risk neuroblastoma. Patients that are diagnosed and stratified as high-risk suffer from relapses and metastases and their survival rate remains below 40% despite intensive multimodal treatment. To date there are only a few driver genes linked to the pathogenesis of high-risk neuroblastoma, most of which are not directly druggable and frequently insufficient response to therapy is observed. In our group, we employ state-of-the-art technologies, such as genome-wide and targeted CRISPR/Cas9 screens and single cell genomics and epigenomics in order to identify the oncogenic drivers and epigenetic dependencies in tumours from high-risk neuroblastoma patients. We have established in vitro and in vivo preclinical patient-derived models for functional assays and drug testing for precision oncology that can be translated into existing and new clinical trials with the ultimate goal to improve treatment outcomes and survival of high-risk neuroblastoma patients.
Tumour heterogeneity and microenvironment
Solid tumours often consist of different subpopulations of cells that harbor distinct genotypes and phenotypes. This results in a variation of clinically important features such as the abundance of prognostic markers and therapeutic targets, leading to differential levels of treatment sensitivity. Tumour cell metastasis and adaptation to new tissue microenvironments can further promote inter- and intratumour heterogeneity among metastasizing and disseminated tumour cells. In support of this notion, we have recently shown that disseminated tumour cells in the bone marrow substantially differ from the tumour they originated from in regards to their genetic makeup and expression programs. Tumour cells disseminate to the bone marrow in various solid cancers such as neuroblastoma, breast cancer and Ewing sarcoma, which is associated with poor outcome. In the majority of metastatic neuroblastoma patients, disseminated tumour cells are present in the bone marrow already at the time point of diagnosis. Our aim is to capture the full spectrum of tumor cells in neuroblastoma and to understand their interaction with the tumor microenvironment at the primary site and in the metastatic bone marrow by using novel single-cell-omics and multiplex imaging technologies. This will allow us to identify new biomarkers and to develop better therapeutics for targeted treatment.
Development of new diagnostics and prognostic markers for precision oncology
Another focus of our group is the translation of current research to clinical practice with the development of better diagnostic approaches and prognostic markers. As pediatric solid tumours are rare, this can only be addressed within the scope of multi-center as well as multi-disciplinary cooperation. Towards this, we are part of different consortia and collaborative studies, that bring together experts in the fields of biological and computer-based research with pediatric oncologists. In addition to molecular profiling of the primary tumor and bone marrow, novel liquid biopsy approaches, i.e. the analysis of tumor markers in body fluids, are important tools to monitor cancer patients and detect relapse early. We employ advanced bioinformatics analyses, AI-based machine-learning and customized visualization strategies on complex multi-dimensional data for identifying novel markers for precision oncology. As an example, we have recently developed the VISIOMICS software platform http://www.visiomics.at/, which supports an integrated analysis of image and multiOMICS data for tumour diagnostics.
Services and facilities
- We work in close collaboration with the Tumour Biology Diagnostic Team, which offers diagnostic services as ISO9001 certified and national reference lab for several ongoing clinical studies. For more information please see: https://www.labdia.at/.
- CCRI Biobank for pediatric solid tumours in collaboration with Labdia.
- Automated imaging devices
Projects and Funding
WWTF LS18-111 Ultra-high-risk pediatric cancer - combinatorial drivers and therapeutic targets for precision medicine https://www.wwtf.at/programmes/life_sciences/LS18-111 Transcan-2/ERA-Net/FWF LIQUIDHOPE Advancing Liquid Biopsies for Monitoring and Personalized Treatment of Children with Neuroblastoma https://www.transcanfp7.eu/index.php/abstract/liquidhope.html EC Horizon2020 PRIMAGE PRedictive In-silico Multiscale Analytics to support cancer personalized diaGnosis and prognosis, Empowered by imaging biomarkers https://cordis.europa.eu/project/id/826494 FFG VISIOMICS Platform supporting an integrated analysis of image and multiOMICs data based on liquid biopsies for tumour diagnostics https://projekte.ffg.at/projekt/2808496 EC Horizon2020 TREL Twinning in Research and Education to improve survival in Childhood Solid Tumours in Lithuania https://cordis.europa.eu/project/id/952438/de
Selected collaboration partners
National: Nikolaus Fortelny (University Salzburg, Austria), Christoph Bock (CeMM/BSF, Austria), Katja Bühler (VRVis, Austria), Alan Hanbury (Technical University Vienna, Research Studios Austria), Lukas Fischer (Software Competence Center Hagenberg, Austria), Michael Brandstötter (CogVis, Austria), Christopher Gerner (University of Vienna, Austria)
International: Hedwig Deubzer (Charite, Germany), Gudrun Schleiermacher (Institute Curie, France), Lieve Tytgat (Princess Maxima Center, Netherlands), Jan Molenaar (Princess Maxima Center, Netherlands), Frank Westermann (DKFZ, Germany), Jaime Font deMora (Research Institute Hospital La Fe, Spain), Adela Canete (University Hospital La Fe, Spain), Barbara Hero (University Clinic Cologne, Germany), Christian Ostalecki (University Clinic Erlangen, Germany), Jelena Racson (Vilnius University Children’s Hospital, Lithunia), Bernd Bodenmiller (ETH Zurich and University of Zurich, Switzerland)
- Daria Lazic, Florian Kromp, Michael Kirr, Filip Mivalt, Fikret Rifatbegovic, Florian Halbritter, Marie Bernkopf, Andrea Bileck, Marek Ussowicz, Inge M Ambros, Peter F Ambros, Christopher Gerner, Ruth Ladenstein, Christian Ostalecki, Sabine Taschner-Mandl. Single-cell landscape of bone marrow metastases in human neuroblastoma unraveled by deep multiplex imaging. bioRxiv 2020.09.30.321539; doi: https://doi.org/10.1101/2020.09.30.321539
Peer-reviewed articles and book chapters
- Tamara Weiss, Sabine Taschner-Mandl, Lukas Janker, Andrea Bileck, Fikret Rifatbegovic, Florian Kromp, Helena Sorger, Maximilian O. Kauer, Christian Frech, Reinhard Windhager, Christopher Gerner, Peter F. Ambros & Inge M. Ambros. Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8. Nature Communication 2021; https://doi.org/10.1038/s41467-021-21859-0
- F. Kromp, L. Fischer, E. Bozsaky, I. Ambros, W. Dörr, K. Beiske, P. Ambros, A. Hanbury, S. Taschner-Mandl. Evaluation of Deep Learning architectures for complex immunofluorescence nuclear image segmentation. IEEE Transactions on Medical Imaging, 2021; doi: 10.1109/TMI.2021.3069558
- Sabine A. Hartlieb, Lina Sieverling, Michal Nadler-Holly, Matthias Ziehm, Umut H. Toprak, Carl Herrmann, Naveed Ishaque, Konstantin Okonechnikov, Moritz Gartlgruber, Young-Gyu Park, Elisa Maria Wecht, Larissa Savelyeva, Kai-Oliver Henrich, Carolina Rosswog, Matthias Fischer, Barbara Hero, David T. W. Jones, Elke Pfaff, Olaf Witt, Stefan M. Pfister, Richard Volckmann, Jan Koster, Katharina Kiesel, Karsten Rippe, Sabine Taschner-Mandl, Peter Ambros, Benedikt Brors, Matthias Selbach, Lars Feuerbach & Frank Westermann. Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome. Nature Communications 2021; doi: https://doi.org/10.1038/s41467-021-21247-8
- Angela Bellini, Ulrike Pötschger, Virginie Bernard, Eve Lapouble, Sylvain Baulande, Peter F. Ambros, Nathalie Auger, Klaus Beiske, Marie Bernkopf, David R. Betts, Jaydutt Bhalshankar, Nick Bown, Katleen de Preter, Nathalie Clement, Valerie Combaret, Jaime Font de Mora, Sally L. George, Irene Jimenez, Marta Jeison, Barbara Marques, Tommy Martinsson, Katia Mazzocco, Martina Morini, Annick Muhlethaler-Mottet, Rosa Noguera, Gaelle Pierron, Maria Rossing, Sabine Taschner-Mandl, Nadine Van Roy, Ales Vicha, Louis Chesler, Walentyna Balwierz, Victoria Castel, Martin Elliott, Per Kogner, Genevieve Laureys, Roberto Luksch, Josef Malis, Maja Popovic-Beck, Shifra Ash, Olivier Delattre, Dominique Valteau-Couanet, Deborah A. Tweddle, Ruth Ladenstein and Gudrun Schleiermacher. Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1). Journal of Clinical Oncology 2021: doi: 10.1200/JCO.21.00086
- Kromp F, Bozsaky E, Rifatbegovic F, Fischer L, Ambros M, Berneder M, Weiss T, Lazic D, Dörr W, Hanbury A, Beiske K, Ambros PF, Ambros IM, Taschner-Mandl S. An annotated fluorescence image dataset for training nuclear segmentation methods. Sci Data. 2020 Aug 11;7(1):262. doi: 10.1038/s41597-020-00608-w. PMID: 32782410; PMCID: PMC7419523.
- Gerber T, Taschner-Mandl S, Saloberger-Sindhöringer L, Popitsch N, Heitzer E, Witt V, Geyeregger R, Hutter C, Schwentner R, Ambros IM, Ambros PF. Assessment of Pre-Analytical Sample Handling Conditions for Comprehensive Liquid Biopsy Analysis. J Mol Diagn. 2020 Aug;22(8):1070-1086. doi: 10.1016/j.jmoldx.2020.05.006. Epub 2020 Jun 1. PMID: 32497717.
- Eghbal-Zadeh H, Fischer L, Popitsch N, Kromp F, Taschner-Mandl S, Gerber T, Bozsaky E, Ambros PF, Ambros IM, Widmer G, Moser BA. DeepSNP: An End-to-End Deep Neural Network with Attention-Based Localization for Breakpoint Detection in Single-Nucleotide Polymorphism Array Genomic Data. J Comput Biol. 2019 Jun;26(6):572-596. doi: 10.1089/cmb.2018.0172. Epub 2018 Dec 26. PMID: 30585743.
- Weiss T, Taschner-Mandl S, Ambros PF, Ambros IM. Detailed Protocols for the Isolation, Culture, Enrichment and Immunostaining of Primary Human Schwann Cells. Methods Mol Biol. 2018;1739:67-86. doi: 10.1007/978-1-4939-7649-2_5. PMID: 29546701.
- Rifatbegovic F, Frech C, Abbasi MR, Taschner-Mandl S, Weiss T, Schmidt WM, Schmidt I, Ladenstein R, Ambros IM, Ambros PF. Neuroblastoma cells undergo transcriptomic alterations upon dissemination into the bone marrow and subsequent tumour progression. Int J Cancer. 2018 Jan 15;142(2):297-307. doi: 10.1002/ijc.31053. Epub 2017 Oct 4. PMID: 28921546; PMCID: PMC5725737
Team Tumour Biology
Collaborating clinicians at St. Anna Children's Hospital and Vienna General Hospital
Ruth Ladenstein, Stefan Fiedler, Caroline Hutter, Elisabeth Salzer, Heidi Boztug, Stefan Köhrer, Leo Kager, Martin Metzelder