23 minute read
12 Research Groups
12
Research Groups
As an academic department, we continuously strive to improve medical care in all aspects. There are 6 university professorships and 10 laboratory research groups associated with MOH. In 2021, MOH raised >CHF 3.4 million in third-party funding and published overall >130 scientific publications in peer-reviewed journals.
We establish interdisciplinary programs in precision oncology, immunotherapies and stem cell transplantation/ cellular therapies, which combine innovative cancer medicine and research. We aim to improve the understanding of cancer biology and pathology to develop effective and individualized treatment concepts for our patients.
Translational Cancer Research Lab
Keywords
TP53, Pre-Malignancies, Clonal Hematopoiesis, Acute Myeloid Leukemia
Aims
We generate novel in vitro and in vivo models of pre-malignancies and overt cancer with a special focus on TP53-mutant hematological (pre-)malignancies. We use human genetics data, precise CRISPR-based genome editing, classical molecular biology as well as large-scale functional genomics to elucidate disease mechanisms and to identify cancer vulnerabilities. Our ultimate goal is to improve outcomes in cancer patients.
Research Highlight
TP53-mutant acute myeloid leukemia (AML) is a distinct clinicogenomic entity characterized by poor responses to conventional induction chemotherapy, high relapse rates, and poor overall survival. The hypomethylating agents (HMAs) decitabine or azacitidine in combination with the BCL2-inhibitor venetoclax have been suggested as promising agents in the treatment of patients with TP53-mutant AML. However, emerging clinical data questions the superiority of this treatment approach. The principal goal of this research project was to unravel the impact of the TP53 mutational status on the response to treatment with HMAs, with or without venetoclax, by taking advantage of CRISPR/Cas9- engineered human isogenic AML models.
TP53 mutations confer increased resistance to hypomethylating agents as well as BCL-2 inhibi-
tion in vitro. (A) Graphical representation of the experimental workflow for generating MOLM13-TP53 isogenic cell lines and MV4-11 and OCI-AML3 TP53 KO cell lines. (B) MOLM13- TP53 isogenic AML cell lines were treated with DMSO, decitabine, azacitidine, or venetoclax at increasing concentrations for 72 hours, after which cell viability was assessed using a CellTiter-Glo luminescent assay (symbols represent averages from 3 independent experiments; error bars indicate standard error of the mean). Schimmer et al. Blood Adv. 2021
Selected Publications (2020–2021)
TP53 mutations confer resistance to hypomethylating agents and BCL-2 inhibition in myeloid neoplasms. Schimmer RR, Kovtonyuk LV, Klemm N, Fullin J, Stolz SM, Mueller J, Caiado F, Kurppa KJ, Ebert BL, Manz MG, Boettcher S. Blood Adv. 2021 Jun 14;6(11):3201-3206 CXCL12-abundant reticular cells are the major source of IL-6 upon LPS stimulation and thereby regulate hematopoiesis. Gerosa RC, Boettcher S, Kovtonyuk LV, Hausmann A, Hardt WD, Hidalgo J, Nombela-Arrieta C, Manz MG. Blood Adv. 2021 Dec 14;5(23):5002-5015 Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome. Kennedy AL, Myers KC, Bowman J, Gibson CJ, Camarda ND, Furutani E, Muscato GM, Klein RH, Ballotti K, Liu S, Harris CE, Galvin A, Malsch M, Dale D, Gansner JM, Nakano TA, Bertuch A, Vlachos A, Lipton JM, Castillo P, Connelly J, Churpek J, Edwards JR, Hijiya N, Ho RH, Hofmann I, Huang JN, Keel S, Lamble A, Lau BW, Norkin M, Stieglitz E, Stock W, Walkovich K, Boettcher S, Brendel C, Fleming MD, Davies SM, Weller EA, Bahl C, Carter SL, Shimamura A, Lindsley RC. Nat Commun. 2021 Feb 26;12(1):1334 An induced pluripotent stem cell model of Fanconi anemia reveals mechanisms of p53-driven progenitor cell differentiation. Marion W, Boettcher S, Ruiz-Torres S, Lummertz da Rocha E, Lundin V, Morris V, Chou S, Zhao AM, Kubaczka C, Aumais O, Zhang Y, Shimamura A, Schlaeger TM, North TE, Ebert BL, Wells SI, Daley GQ, Rowe RG. Blood Adv. 2020 Oct 13;4(19):4679-4692 Clonal Hematopoiesis in Hospitalized Elderly Patients With COVID-19. Hameister E, Stolz SM, Fuhrer Y, Thienemann F, Schaer DJ, Nemeth J, Schuepbach RA, Goede J, Reinhart S, Schmidt A, Kahraman A, Schmid M, Moch H, Zoche M, Manz MG, Balabanov S, Boettcher S. Hemasphere. 2020 Aug 10;4(4):e453
Steffen Böttcher
steffen.boettcher@usz.ch
Research Group Members (A–Z)
– Jonas Fullin,
MSc/PhD candidate – Erik Hameister,
MD/Postdoctoral Research
Fellow – Nancy Klemm,
MSc/PhD candidate – Christian Koch,
MD (Physician-scientist) – Nils Konrad, cand. med./Master student – Roman Schimmer,
MD/Physician-scientist – Sebastian Stolz,
MD/Physician-scientist – Ebru Topçu,
MSc/PhD candidate
Funding
Our research is supported by the Swiss National Science Foundation, Swiss Cancer League, Fondation Peter Anton & Anna Katharina Miescher, Promedica Foundation, Helmut Horten Foundation, and the ItenKohaut Foundation.
Christian Britschgi
christian.britschgi@usz.ch
Research Group Members (A–Z)
– Lorenz Bankel, MD – Larissa Isenegger, MMed – Laura Leuenberger,
MSc/PhD candidate – Elisa Zaninotto, MD
Funding
Our research is supported by Krebsliga Zürich, Stiftung zur Krebsbekämpfung, Iten-Kohaut Stiftung (USZ Foundation).
Experimental Oncology (Sarcoma) Lab
Keywords
Soft Tissue Sarcomas (STS), Clear Cell Sarcoma (CCSA), ex vivo Drug Profiling, IBDS-SARC
Aims
We aim to explore novel approaches to therapeutically target clear cell sarcoma, a rare soft tissue sarcoma subtype. in collaboration with ETH Zurich (Prof. Berend Snijder), we aim to establish an ex vivo drug screening platform for patients with soft tissue sarcomas (IBDS-SARC) and malignant effusions (malignant fluid samples trial).
Research Highlight
SOX10 is a neural crest transcription factor, which is crucial for maintenance of malignant melanoma. We have shown that activation of WNT signaling – by pharmacologic inhibition of its negative regulator GSK3α/β – leads to proteasome-mediated degradation of SOX10 in melanoma. This induces to cell death and reduces tumor growth in vivo. Clear Cell Sarcoma (CCSA) is a SOX10-dependent soft tissue sarcoma subtype and we are currently exploring mechanisms to suppress SOX10 in CCSA.
(A) Schemactic depicting the identified pathway of how WNT signaling suppresses SOX10 in melanoma. (B) Proteasome inhibition using MG132 rescues the CHIR-mediated suppression of SOX10 in melanoma cells M111031. (C) Tumor growth kinetics with and without CHIR treatment in xenografts established from melanoma cells M111031 in BALB/c-nude mice. Uka et al. Oncogene. 2020
Selected Publications (2020–2021)
Temporal activation of WNT/beta-catenin signaling is sufficient to inhibit SOX10 expression and block melanoma growth. Uka R, Britschgi C, Krattli A, Matter C, Mihic D, Okoniewski MJ, Gualandi M, Stupp R, Cinelli P, Dummer R, Levesque MP, Shakhova O. Oncogene. 2020 May; 39(20):4132-4154 Establishment of an Academic Tissue Microarray Platform as a Tool for Soft Tissue Sarcoma Research. Lee C-J, Wozniak A, Van Cann T, Timmermans I, Wellens J, Vanleeuw U, Briaire-de Bruijn IH, Britschgi C, Bovée JVMG, Zlobec I, Sciot R, Schöffski P. Sarcoma. 2021 March 15:6675260 When SUV Matters: FDG PET/CT at Baseline Correlates with Survival in Soft Tissue and Ewing Sarcoma. Hack RI, Becker AS, Bode-Lesniewska B, Exner GU, Muller DA, Ferraro DA, Warnock GI, Burger IA, Britschgi C. Life (Basel). 2021 Aug 24;11(9):869
Translational Oncology Lab
Keywords
Lung Cancer, Mesothelioma, Immunotherapy, Targeted-Treatments, Clinical Trial Develop- ment
Aims
Our research focus is evaluating new combinatorial treatments and their underlying mechanisms of action and resistance in patients with mesothelioma and lung cancer.
Research Highlight
We have demonstrated the expression of an immunecheckpoint inhibitor (PD-L1) in mesothelioma tumor samples (P. Tallon de Lara CCR 2018). Based on these data we have developed under the umbrella of the European Thoracic Oncology Platform (ETOP) a randomized phase III clinical trial comparing the use of an immunotherapy (pembrolizumab, an anti-PD) and chemotherapy in patients with pleural mesothelioma (S. Popat, Annals of Oncology 2020). Further, based on our preclinical data, we have developed a clinical trial investigating the use of a new treatment approach. In this study, patients with advanced pleural mesothelioma and lung cancer resistant to immunotherapy have been included (SAKK17/18). The related translational research to this study is ongoing in our laboratory.
Trial design and flow chart of the PROMISE-meso trial. Popat et al. Ann Oncol. 2020
Selected Publications (2020–2021)
Real-world treatment patterns and survival outcome in advanced anaplastic lymphoma kinase rearranged non-small-cell lung cancer patients. Britschgi C, Rechsteiner M, Delaloye R, Früh M, Metro G, Banini M, Gautschi O, Rothschild SI, Wild PJ, Banna GL, Curioni-Fontecedro A. Front Oncol. 2020 Aug 21;10:1299 A multicentre randomised phase III trial comparing pembrolizumab vs single agent chemotherapy for advanced pre-treated malignant pleural mesothelioma – results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial. Popat S, Curioni-Fontecedro A, Dafni U, Shah R, O’Brien M, Pope A, Fisher P, Spicer J, Roy A, Gilligan D, Gautschi O, Nadal E, Janthur WD, López Castro R, García Campelo R, Rusakiewicz S, Letovanec I, Polydoropoulou V, Roschitzki-Voser H, Ruepp B, Gasca-Ruchti A, Peters S, Stahel RA :Equal contribution. Ann Oncol. 2020 Dec;31(12):1734-1745 Local delivery of CAR T cells targeting fibroblast activation protein is safe in patients with pleural mesothelioma: first report of FAPME, a phase I clinical trial. Hiltbrunner S, Britschgi C, Schuberth P, Bankel L, Nguyen-Kim TDL, Gulati P, Weder W, Opitz I, Lauk O, Caviezel C, Bachmann H, Tabor A, Schröder P, Knuth A, Münz C, Stahel R, Boyman O, Renner C, Petrausch U, Curioni-Fontecedro A. Ann Oncol. 2021 Jan;32(1):120-121 Sotorasib for Lung Cancers with KRAS p.G12C Mutation. Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, Italiano A, Schuler M, Borghaei H, Barlesi F, Kato T, Curioni-Fontecedro A, Sacher A, Spira A, Ramalingam SS, Takahashi T, Besse B, Anderson A, Ang A, Tran Q, Mather O, Henary H, Ngarmchamnanrith G, Friberg G, Velcheti V, Govindan R. N Engl J Med. 2021 Jun 24;384(25):2371-2381 Tumor Immune Microenvironment and genetic alterations in mesothelioma. Hiltbrunner S, Mannarino L, Kirschner MB, Opitz I, Rigutto A, Laure A, Lia M, Nozza P, Marconi A, Marchini S, D’Incalci M, Curioni-Fontecedro A, F. Grosso. Front Oncol. 2021 Jun 23;11:660039
Alessandra Curioni
alessandra.curioni@usz.ch
Research Group Members (A–Z)
– Stefanie Hiltbrunner, PhD – Alexander Laure,
MSc/PhD candidate – Angelica Rigutto,
MSc/PhD candidate
Funding
Our research is supported by SAKF, Krebsliga, Olga Mayenfish Stiftung, Kurt and Senta Hermann Stiftung.
Ralph Fritsch
ralph.fritsch@usz.ch
Research Group Members (A–Z)
– Dilara Akhoundova, MD – Saskia Hussung, MD – Rhena Klar, MSc (Freiburg D) – Mia Roth, BSc – Bianca de Nard, cand. med.
Funding
Our research is supported by Iten-Kohaut Foundation, Innovationspool USZ, Stiftung für klinische Forschung, Novartis Foundation, Science Foundation for Oncology, Deutsche Forschungsgemeinschaft, Fördergesellschaft Forschung Tumobiologie (Freiburg (D)).
Translational GI Oncology Lab
Keywords
Gastrointestinal Cancer, Precision Treatment, Oncogenic Signalling, Organoid Modelling, Liquid Biopsy
Aims
To advance precision treatment of gastrointestinal and hepato-pancreatico-biliary (HPB) tumors. To establish a cutting-edge GI Oncology program integrating basic, translational and clinical research.
Research Highlight
Definition of integrated subgroups or colorectal cancer: In an interdisciplinary effort, we established a novel, clinically relevant classification of integrated molecular subgroups of metastatic colorectal cancer.
Integrated subgroups of metastatic colorectal cancer. Schematic depicts seven distinct clinicopathological subgroups of metastatic colorectal cancer with prognostic and predictive significance for precision treatment. Petrowsky et al. Nat Rev Gastroenterol Hepatol. 2020
Selected Publications (2020–2021)
Targeting Secondary and Tertiary Resistance to BRAF Inhibition in BRAF V600E-Mutated Metastatic Colorectal Cancer. Akhoundova D, Pietge H, Hussung S, Kiessling M, Britschgi C, Zoche M, Rechsteiner M, Weber A, Fritsch RM. JCO Precis Oncol 2021 Nov;5:1082-1087 Longitudinal analysis of cell-free mutated KRAS and CA 19-9 predicts survival following curative resection of pancreatic cancer. Hussung S, Akhoundova D, Hipp J, Follo M, Klar RFU, Philipp U, Scherer F, von Bubnoff N, Duyster J, Boerries M, Wittel U, Fritsch RM. BMC cancer 202; 21:49 Perioperative cell-free mutant KRAS dynamics in patients with pancreatic cancer. Hipp J, Hussung S, Timme-Bronsert S, Boerries M, Biesel E, Fichtner-Feigl S, Fritsch RM, Wittel UA. Br J Surg 2021;108:239243 Modern therapeutic approaches for the treatment of malignant liver tumours. Petrowsky H, Fritsch RM, Guckenberger M, De Oliveira ML, Dutkowski P, Clavien P. A. Nat Rev Gastroenterol Hepatol 2022; 17:755-772 Development and Clinical Validation of Discriminatory Multitarget Digital Droplet PCR Assays for the Detection of Hot Spot KRAS and NRAS Mutations in Cell-Free DNA. Hussung S, Follo M, Klar RFU, Michalczyk S, Fritsch K, Nollmann F, Hipp J, Duyster J, Scherer F, von Bubnoff N, Boerries M, Wittel U, Fritsch RM. J Mol Diagn 2022;22:943-956
Cellular Immunotherapies
Keywords
Cancer Immunotherapy, Gene Therapy, Hematological Malignancies, Chimeric Antigen Receptor T cells, Cellular Therapy
Aims
Our research focuses on immunotherapy and uses genetic engineering to unleash our immune system against cancer. Specifically, we aim to apply non-viral engineering to generate next-generation CAR T cells.
Research Highlight
Chimeric antigen receptor (CAR) T cell immunotherapy has resulted in complete remission and durable response in highly refractory patients. This is the first study using donorderived anti-CD19 CAR T cells generated with Sleeping Beauty (SB) transposon in B-cell acute lymphoblastic leukemia (B-ALL) patients relapsed after HSCT, demonstrating that non-viral vectors and donor cells can be used to achieve treatment of patients with fulminant relapse.
Schematic outline depicting the study design of the clinical trial. Magnani et al. J Clin Invest. 2020
Selected Publications (2020–2021)
Transposon-Based CAR T Cells in Acute Leukemias: Where are We Going? Magnani CF, Tettamanti S, Alberti G, Pisani I, Biondi A, Serafini M, Gaipa G., Cells. 2020 May 27;9(6):1337 Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells. Myburgh R, Kiefer JD, Russkamp NF, Magnani CF, Nuñez N, Simonis A, Pfister S, Wilk CM, McHugh D, Friemel J, Müller AM, Becher B, Münz C, van den Broek M, Neri D, Manz MG. Leukemia. 2020 Oct;34(10):2688-2703 Targeting CD33 in Chemoresistant AML Patient-Derived Xenografts by CAR-CIK Cells Modified with an Improved SB Transposon System. Rotiroti MC, Buracchi C, Arcangeli S, Galimberti S, Valsecchi MG, Perriello VM, Rasko T, Alberti G, Magnani CF, Cappuzzello C, Lundberg F, Pande A, Dastoli G, Introna M, Serafini M, Biagi E, Izsvák Z, Biondi A, Tettamanti S. Mol Ther. 2020 Sep 2;28(9):1974-1986 Sleeping Beauty-engineered CAR T cells achieve anti-leukemic activity without severe toxicities. Magnani CF, Gaipa G, Lussana F, Belotti D, Gritti G, Napolitano S, Matera G, Cabiati B, Buracchi C, Borleri G, Fazio G, Zaninelli S, eTettamanti S, Cesana S, Colombo V, Quaroni M, Cazzaniga G, Rovelli A, Biagi E, Galimberti S, Calabria A, Benedicenti F, Montini E, Ferrari S, Introna M, Balduzzi A, Valsecchi MG, Dastoli G, Rambaldi A, Biondi A. J Clin Invest. 2020 Nov 2;130(11):6021-6033 The past, present, and future of non-viral CAR T cells. Moretti A, Ponzo M, Nicolette CA, Tcherepanova IJ, Biondi A, Magnani CF. Front. Immunol. 2022 Jun 9;13:867013
Chiara Magnani
chiara.magnani@usz.ch
Research Group Members (A–Z)
– Silvan Brunn,
PhD candidate – Morgane Chambovey,
PhD candidate – Alessandro Menapace,
MSc student – Marianna Ponzo,
PhD candidate
Funding
Our research is supported by the Swiss National Science Foundation, the San Salvatore Foundation, Cancer Research UK, AIRC.
Markus G. Manz
markus.manz@usz.ch
Research Group Members (A–Z)
– Francisco Caiado, PhD – Anne Kaiser, MD – Jonathan Kiefer, PhD – Larisa V. Kovtonyuk, PhD – Chiara Magnani, PhD – Maddalena Marconato,
MD PhD – Jan Müller, MD – Renier Myburgh, PhD – Christian Pellegrino, PhD – Norman Russkamp, MD – Gianluca Spaltro, MD PhD – Syndi Uhlig, Labmanager – Laura Volta, PhD – Matthias Wilk, MD
Funding
Our research is supported by the Swiss National Science Foundation, the Krebsforschung Schweiz, Innosuisse, the Clinical Research Priority Program “ImmunoCure” of the University of Zurich, the Hochschulmedizin University of Zürich flagship program “ImmunoTargET”, and Wyss Zürich.
Experimental Hematology and Immunology Lab
Keywords
Hematopoietic Stem Cells, Hematopoiesis, Hematopoietic Ageing, Hematopoietic Stem Cell Malignancies, Immunotherapy of Cancer
Aims
We aim to gain knowledge on healthy and malignant hematopoietic stem cells in order to develop new medical interventions for prevention and cure of hematopoietic stem cell disease. We develop and use engineered immunotherapies with the aim to fight hematopoietic and solid organ cancers more specifically and effectively.
Research Highlight
In hematologic malignancies, currently successful immunotherapies are directed against lineage-specific cell surface antigens. We generated CAR T-cells with specificity against CD117, the cognate receptor for stem cell factor. Anti-CD117 CAR T-cells efficiently targeted healthy and leukemic CD117-positive cells in vitro and in vivo. This study provides the basis for further developing immunotherapies against HSPCs and their malignant derivates.
Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells. Myburgh et al. Leukemia. 2020
Selected Publications (2020–2021)
Clonal hematopoiesis in donors and long-term survivors of related allogeneic hematopoietic stem cell transplantation. Boettcher S, Wilk CM, Singer J, Beier F, Burcklen E, Beisel C, Ventura Ferreira MS, Gourri E, Gassner C, Frey BM, Schanz U, Skoda RC, Ebert BL, Brummendorf TH, Beerenwinkel N, Manz MG. Blood. 2020 Apr 30;135(18):1548-1559 Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells. Myburgh R, Kiefer JD, Russkamp NF, Magnani CF, Nuñez N, Simonis A, Pfister S, Wilk CM, McHugh D, Friemel J, Müller AM, Becher B, Münz C, van den Broek M, Neri D, Manz MG. Leukemia. 2020 Oct;34(10):2688-2703 Impact of Ligand Size and Conjugation Chemistry on the Performance of Universal Chimeric Antigen Receptor T-Cells for Tumor Killing. Pellegrino C, Favalli N, Sandholzer M, Volta L, Bassi G, Millul J, Cazzamalli S, Matasci M, Villa A, Myburgh R, Manz MG, Neri D. Bioconjug Chem. 2020 Jul 15;31(7):17751783 Disruption of CSF-1R signaling inhibits growth of AML with inv(16). Simonis A, Russkamp NF, Mueller J, Wilk CM, Wildschut MHE, Myburgh R, Wildner-Verhey van Wijk N, Mueller R, Balabanov S, Valk PJM, Theocharides APA, Manz MG. Blood Adv. 2021 Mar 9;5(5):1273-1277 Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection. Caiado F, Pietras EM, Manz MG. J Exp Med. 2021 Jul 5;218(7):e20201541
Experimental Hematology Lab
Keywords
Hematopoiesis, Bone Marrow Microenvironment, Hematopoietic Stem Cell Niche, 3D imaging, Malignancies
Aims
We aim to understand how the functional crosstalk of stromal, immune, and hematopoietic progenitor cells regulates hematopoiesis in health and disease. We have a special interest in defining how the tissue mciroenvironment of hematopoietic organs and hematopoietic stem cell niches are perturbed inflammatory conditions, infections, ageing and cancer, and how these alterations lead to hematological diseases.
Research Highlight
Our recent studies demonstrate that chronic viral infection causes durable destruction of bone marrow mesenchymal stromal networks , leading to long-lasting impairment of the competitive fitness of HSCs. In vivo blockage of IFN pathways protects bone marrow and HSC function from viral-induced damage.
Graphically depicts the main findings of our studies. Isringhausen et al. J Exp Med. 2021
Selected Publications (2020–2021)
CD8 T cells induce destruction of bone marrow stromal niches and hematopoietic stem cell dysfunction in chronic viral infections. Isringhausen S , Suessbier U, Kovtonyuk L , Kraeutler N, Helbling PM, Gomariz-Carillo A, Wong, HC, Nagasawa T, Manz M, Oxenius A, Nombela-Arrieta C. J Exp Med. 2021, 218(12):e20192070 Modality attention and sampling enables deep learning with heterogeneous marker combinations in fluorescence microscopy. Gomariz A, Portenier T, Helbling PM, Isringhausen S, Suessbier U, NombelaArrieta, C, Goksel O. co-last and senior author. Nat Mach Intell. 2021 Sep;3(9):799-811 Spatial analysis of hematopoietic stem cell niches. Gomariz A, Isringhausen S, Helbling P, Nombela- Arrieta C. Annals of the New York Academy of Sciences 2020 Apr;1466(1):5-16 Combined single-cell and spatial transcriptomics reveals fundamental principles of bone marrow niche organization. Baccin C, Al-Sabah J, Velten L, Helbling P, Nombela-Arrieta C, Steinmetz LM, Trumpp A, Haas S. Nat Cell Biol. 2020 Jan;22(1):38-48 Global transcriptomic profiling of the bone marrow stromal microenvironment during postnatal development, aging and inflammation. Helbling PM, Piñeiro-Yáñez E, Gerosa R, Boettcher S, Al-Shahrour S, Manz MG, Nombela-Arrieta C. Cell Rep. 2019 Dec 3;29(10):3313-3330.e4
César Nombela Arrieta
cesar.nombelaarrieta@usz.ch
Research Group Members (A–Z)
– Serena Fazio, Msc – Serena Galli, MD – Álvaro Gomariz, PhD – Patrick Helbling, PhD – YeVin Mun, Msc – Angelina Oestmann,
Dr. med. vet. – Ana Luisa Pereira, MD – Flavian Thelen, PhD – Anjali Vijaykumar, Msc
Funding
Our research is supported by Swiss National Foundation, European Research Council Consolidator Grant program (ERC-CoG), Krebsforschung Schweiz, Clinical Research Priority Programs University of Zurich (CRPP), Novartis Foundation, Promedica Foundation, Krebsliga Zurich and Theodor-Egli Stiftung.
Alexandre Theocharides
alexandre.theocharides@usz.ch
Research Group Members (A–Z)
– Lisa Dietsche, PhD cand. – Mara Hofstetter, PhD cand. – Stefanie Kreutmair, MD – Veronika Lysenko, PhD – Patrick Schürch, PhD – Thijs Wildschut, PhD
Funding
Our research is supported by the Swiss National Science Foundation, the Swiss Cancer League, the USZ foundation, the Iten Kohaut foundation, and the Gossweiler foundation. Alexandre Theocharides is supported by the Cloëtta foundation.
Translational Hematology Lab
Keywords
Macrophage Immune Checkpoints, CD47, Myeloproliferative Neoplasms, Immunotherapy, Calreticulin
Aims
We aim to identify combination partners for macrophage immune checkpoints inhibition and improve our understanding of diseased macrophages. Our preclinical models are the basis for the development of future clinical trials. Furthermore, we are interested in the molecular mechanisms that contribute to myeloproliferative neoplasms.
Research Highlight
We developed a patient-derived xenograft model for patients with myeloproliferative neoplasms (MPNs), more precisely myelofibrosis (MF). In this model, we could demonstrate the development of MF in humanized mice (MISTRG) is significantly improved in comparison to other mouse strains. This model is also suited for the investigation of novel treatments.
Development of human atypical megakaryocytes and myelofibrosis in the bone marrow of MISTRG mice transplanted with a MF patient sample. The patient bone marrow sample is shown on the right as a comparison. Arrows and arrowheads point to atypical megakaryocytes. H&E, Hematoxylin & Eosin; hCD61+, staining for human megakaryocytes; Gömöri, staining for reticulin fibers. HD, healthy donor; PT, patient. In contrast to MISTRG mice transplanted with a HD sample atypical megakaryocytes and an increase in reticulin fibers is observed in MISTRG mice transplanted with a MF patient sample. Lysenko et al. Bood Adv. 2020
Selected Publications (2020–2021)
Enhanced engraftment of human myelofibrosis stem and progenitor cells in MISTRG mice. Lysenko V, Wildner-Verhey van Wijk N, Zimmermann K, Weller M, Bühler M, Wildschut M, Schürch P, Fritz C, Wagner U, Calabresi L, Psaila B, Flavell R, Vannucchi A, Mead A, Wild P, Dirnhofer S, Manz MG, Theocharides A. Blood Adv. 2020 Jun 9;4(11):2477-2488 Editorial: Advances in Human Immune System Mouse Models for Studying Human Hematopoiesis and Cancer Immunotherapy. Saito Y, Willinger T, Theocharides A. Front Immunol. 2021 Dec 23;12:829644 The Tumor Profiler Study: integrated, multi-omic, functional tumor profiling for clinical decision support. Irmisch A, Bonilla X, Chevrier S, Lehmann KV, Singer F, Toussaint NC, Esposito C, Mena J, Milani ES, Casanova R, Stekhoven DJ, Wegmann R, Jacob F, Sobottka B, Goetze S, Kuipers J, Sarabia Del Castillo J, Prummer M, Tuncel MA, Menzel U, Jacobs A, Engler S, Sivapatham S, Frei AL, Gut G, Ficek J, Miglino N; Tumor Profiler Consortium, Aebersold R, Bacac M, Beerenwinkel N, Beisel C, Bodenmiller B, Dummer R, Heinzelmann-Schwarz V, Koelzer VH, Manz MG, Moch H, Pelkmans L, Snijder B, Theocharides A, Tolnay M, Wicki A, Wollscheid B, Rätsch G, Levesque MP. Cancer Cell. 2021 Mar 8;39(3):288-293.:co-last author Reduced CXCL4/PF4 expression as a driver of increased human hematopoietic stem and progenitor cell proliferation in polycythemia vera. Meier-Abt F, Wolski WE, Tan G, Kummer S, Amon S, Manz MG, Aebersold R, Theocharides A. Blood Cancer J. 2021 Feb 11;11(2):31 A patient with a germline GATA2 mutation and primary myelofibrosis. Rütsche CV, Haralambieva E, Lysenko V, Balabanov S, Theocharides A. Blood Adv. 2021 Feb 9;5(3):791-795
Experimental Oncology Lab
Keywords
Oncology, Precision Medicine, Therapy Prediction, Functional and Multi-Omics Testing
Aims
The Experimental Oncology Research Group has a focus on improving therapy outcomes in oncology by combining deep analysis of tumor tissue (functional & single-cell omics) with state-of-the-art data science.
Research Highlight
Using modern analytical platforms, several tens of thousands of tumor attributes can be assessed from a little piece of tissue within around two weeks. This significant technological progress has paved the way to make multi –omics approaches usable for individual therapy prediction. By connecting deep biological analysis with large clinical databases, modelling of therapy response and benefit is possible with an unprecedented accuracy.
The Tumor Profiler Trial: the study workflow entails patient enrollment, sample collection, analysis by different technology platforms and data integration, creation and discussion of molecular research and summary reports, discussion of treatment options in pre-tumor boards, the final treatment decision and assessment of outcome. Irmisch et al. Cancer Cell. 2021
Selected Publications (2020–2021)
Results of the phase I open label clinical trial SAKK 06/14 assessing safety of intravesical instillation of VPM1002BC, a recombinant mycobacterium Bacillus Calmette Guérin (BCG), in patients with non-muscle invasive bladder cancer and previous failure of conventional BCG therapy. Rentsch CA, Bosshard P, Mayor G, Rieken M, Püschel H, Wirth G, Cathomas R, Parzmair GP, Grode L, Eisele B, Sharma H, Gupta M, Gairola S, Shaligram U, Goldenberger D, Spertini F, Audran R, Enoiu M, Berardi S, Hayoz S, Wicki A. Oncoimmunology 2020; 9(1):e1748981 The Tumor Profiler Study: Integrated, multi-omic, functional tumor profiling for clinical decision support. Irmisch A, Bonilla X, Chevrier S, Lehmann KV, Singer F, Toussaint NC, Esposito C, Mena J, Milani ES, Casanova R, Stekhoven DJ, Wegmann R, Jacob F, Sobottka B, Goetze S, Kuipers J, Sarabia Del Castillo J, Prummer M, Tuncel MAA, Menzel U, Wicki A, …, Levesque MP. Cancer Cell 2021;39(3):288-293.
Andreas Wicki
andreas.wicki@usz.ch
Research Group Members (A–Z)
– Laura Boos, MD – Danny Kupka, MD – Nicola Miglino, PhD – Parisa Rahimzadeh,
PhD cand. – Alexander Ring, MD, PhD
Funding
Our research is supported by the Swiss National Science Foundation, the strategic focus area of Personalized Health & Related Technologies ETH Zurich, the Swiss Personalized Oncology National Data Stream, the Swiss Cancer League, the Swiss Foundation for Clinical Cancer Research (SSKK), the Promedica Foundation, and the University of Zurich.
Thorsten Zenz
thorsten.zenz@usz.ch lymphomaresearchzurich.com
Research Group Members (A–Z)
– Ester Cannizzaro, PhD – Thi Huong Lan Do,
PhD candidate – Jarno Kivioja, PhD – Sandra Kummer,
Biomed. Analyst – Fabienne Christine
Meier-Abt, MD/PhD – Stefanie Reisenauer,
PhD candidate – Marco Roncador,
MD/MSc
Funding
Our research is supported by The Loop Zurich, Krebsliga, Promedica, Leukemia Lymphoma Society, UZH CRPP, and CCCZ.
Lymphoma Research Lab
Keywords
Precision Medicine, CLL, Drug Screening, Omics Profiling, Functional Genomics
Aims
To develop rational and biology-based ways for patient benefit from advances in molecular understanding and targeted drug treatment, we pursue an innovative strategy based on the comprehensive mapping and understanding of individual cancers’ vulnerability to compounds, pathway inhibitors and drugs as well as genome-wide silencing triggers (RNAi, CRISPR). We classify disease based on pathway sensitivity and the systematic understanding of underlying molecular networks.
OXPHOS activity in chronic lymphocytic leukemia: We devised a method for simultaneous subgroup discovery across multiple data types and applied it to genomic, transcriptomic, DNA methylation and ex vivo drug response data from 217 patients with chronic lymphocytic leukemia (CLL). We uncovered a biological axis that captures the proliferative drive (PD) of CLL cells, as it associates with lymphocyte doubling rate, global hypomethylation, accumulation of driver aberrations and response to pro-proliferative stimuli. CLL–PD was linked to the activation of mTOR–MYC–oxidative phosphorylation through transcriptomic, proteomic and single-cell resolution analysis.
Characterization of CLL proliferation at single-cell resolution: Multivariate logistic regression of the proliferation associated markers in CLL. Lu et al. Nature Cancer 2021
Selected Publications (2020–2021)
Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia. Lu J, Cannizzaro E, Meier-Abt F, …., Bodenmiller B, Dietrich S, Oakes C, Zenz T, Huber W. Nature Cancer 2021 Aug;2(8): 853–864 The Protein Landscape of Chronic Lymphocytic Leukemia (CLL). Meier-Abt F, Lu J, Cannizzaro E, Pohly MF, Kummer S, Pfammatter S, Kunz L, Collins BC, Nadeu F, Lee KS, Xue P, Gwerder M, Roiss M, Hüllein J, Scheinost S, Dietrich S, Campo E, Huber W, Aebersold R, Zenz T. Blood 2021 Jun 29;138(24): 2514–2525 SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma. Wilke AC, Doebele C, Zindel A, …… Staudt LM, Zenz T, Oellerich T. Blood 2020 Oct 8;138(4):538-553 Combinatorial drug-microenvironment interaction mapping reveals cell-extrinsic drug resistance mechanisms and clinically relevant patient subgroups in CLL. Bruch PM, Giles H, Kolb C, Herbst SA, Becirovic T, Roider T, Lu J, Scheinost S, Wagner L, Huellein J, Berest I, Kriegsmann M, Kriegsmann K, Zgorzelski C, Dreger P, Zaugg JB, Müller-Tidow C, Zenz T, Huber W, Dietrich S. bioRxiv 2021.07.23.453514 Subgroup-specific gene expression profiles and mixed epistasis in chronic lymphocytic leukemia. Lütge A, Lu J, Hüllein J, Walther T, Sellner L Wu B, Rosenquist R, Oakes CC, Dietrich S, Huber W, Zenz T. bioRxiv 2021.04.16.440134
