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Regulators of cardiac progenitor cells: Focus on cancer drug targets

Applicant Kuster Gabriela
Number 156953
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Cardiovascular Research
Start/End 01.01.2016 - 31.03.2019
Approved amount 479'188.00
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Keywords (5)

Hematopoietic cytokines; Heart Failure; Cardiac progenitor cells; Cardiotoxicity; Cardiomyopathy

Lay Summary (German)

Lead
Die therapeutische Hemmung von Signalwegen, die zur Vermehrung und zum Überleben von Tumorzellen beitragen, kann auch zu Zellverlust in extra-tumoralem Gewebe führen. Aufgrund des limitierten Regenerationspotentials ist das Herz besonders davon betroffen. Entsprechend sind Herzmuskelschädigung und Herzschwäche bekannte, schwere Komplikationen von Krebsbehandlungen. Unsere Studien zielen auf ein verbessertes Verständnis der molekularen Mechanismen dieser Herzschädigung ab, und tragen somit zur Identifikation neuer Zielmoleküle für die Behandlung der Herzschwäche bei.
Lay summary

Inhalt und Ziel des Forschungsprojektes: Fms-like tyrosine kinase 3 (Flt3) ist ein Zielmolekül von Rezeptor Tyrosin Kinase Inhibitoren, die zur Behandlung solider Tumoren und Leukämien eingesetzt werden. Sein physiologischer Ligand FL ist ein hämatopoietisches Zytokin, welches Überleben, Proliferation und Differenzierung von Blutvorläuferzellen reguliert. Wir haben kürzlich die Expression von Flt3 auf Herzmuskelzellen und kardialen Vorläuferzellen nachgewiesen und herausgefunden, dass Flt3 eine zellprotektive Wirkung im ischämischen Maus-Herzen hat. Im vorliegenden Projekt untersuchen wir nun, ob und wie sich die Hemmung von Flt3 auf Herzvorläuferzellen und die Herzfunktion auswirkt.

Relevanz: Mit der Verbesserung des Patientenüberlebens durch neue Krebstherapeutika nehmen kardiale Nebenwirkungen an Bedeutung zu. Ein besseres Verständnis der molekularen Mechanismen ist notwendig, um die interdisziplinäre Behandlung dieser Patienten und das Nebenwirkungsprofil neuer Krebs-Medikamente zu verbessern. Andererseits ermöglichen diese Studien, neue Zielmoleküle für die Behandlung der Herzinsuffizienz zu identifizieren, indem sich durch Stimulation solcher Signalwege das Zellüberleben und die Regeneration von Herzgewebe verbessern lassen könnten.

 

 

Direct link to Lay Summary Last update: 31.08.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129
Gomes Clarissa, Ágg Bence, Andova Andrejaana, Arslan Serdal, Baker Andrew, Barteková Monika, Beis Dimitris, Betsou Fay, Wettinger Stephanie, Bugarski Branko, Condorelli Gianluigi, Silva Gustavo, Danilin Sabrina, Gonzalo-Calvo David, Buil Alfonso, Carmo-Fonseca Maria, Enguita Francisco, Felekkis Kyriacos, Ferdinandy Peter, Gyöngyösi Mariann, Hackl Matthias, Karaduzovic-Hadziabdic Kanita, Hellemans Jan, Heymans Stephane, et al. (2019), Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129, in Non-Coding RNA, 5(2), 31-31.
Chronic heart failure: advances in pharmacological treatment and future perspectives
Kuster Gabriela M., Pfister Otmar (2019), Chronic heart failure: advances in pharmacological treatment and future perspectives, in Swiss Medical Weekly, w20036.
Induction of Endothelial Differentiation in Cardiac Progenitor Cells Under Low Serum Conditions
Mochizuki Michika, Della Verde Giacomo, Soliman Habiba, Pfister Otmar, Kuster Gabriela M. (2019), Induction of Endothelial Differentiation in Cardiac Progenitor Cells Under Low Serum Conditions, in Journal of Visualized Experiments, (143), 1.
Polo-Like Kinase 2 is Dynamically Regulated to Coordinate Proliferation and Early Lineage Specification Downstream of Yes-Associated Protein 1 in Cardiac Progenitor Cells.
Mochizuki Michika, Lorenz Vera, Ivanek Robert, Della Verde Giacomo, Gaudiello Emanuele, Marsano Anna, Pfister Otmar, Kuster Gabriela M (2017), Polo-Like Kinase 2 is Dynamically Regulated to Coordinate Proliferation and Early Lineage Specification Downstream of Yes-Associated Protein 1 in Cardiac Progenitor Cells., in Journal of the American Heart Association, 6(10), e005920.
Fortune Favors the Prepared: Safety and Efficacy of Allogeneic Hypoxia Preconditioned Mesenchymal Stromal Cells in Primates.
Kuster Gabriela M, Liao Ronglih (2016), Fortune Favors the Prepared: Safety and Efficacy of Allogeneic Hypoxia Preconditioned Mesenchymal Stromal Cells in Primates., in Circulation research, 118(6), 908-910.
Cell Therapy for Cardiac Regeneration
Kuster Gabriela M, Della Verde Giacomo, Liao Ronglih, Pfister Otmar (2016), Cell Therapy for Cardiac Regeneration, in Laurence Jeffrey (ed.), Academic Press, Elsevier Inc., United States of America, 265-283.

Collaboration

Group / person Country
Types of collaboration
Dr. A. Wicki, Onkologie, Universitätsspital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
PD Dr. B.A. Kaufmann, Departement Biomedizin Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. A. Wodnar-Filipowicz, Universität Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. A. Rolink, Departement Biomedizin Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
2nd COST Action CardioRNA MC and WG meeting Talk given at a conference Cancer kinases in cardiac homeostasis 13.02.2019 Lisbon, Portugal Kuster Gabriela;
Department of Biomedicine PhD 6th Scientific Retreat Poster The fms-like tyrosine kinase 3-targeting receptor inhibitor quizartinib decreases cardiomyocyte viability in vitro and in vivo 07.06.2018 Einsiedeln, Switzerland Monogiou Belik Daria;
Cardiovascular Research Meeting 2018 Talk given at a conference Regulation of polo-like kinase 2 in cardiomyocytes 15.03.2018 Fribourg, Switzerland Kuster Gabriela; Lorenz Vera; Monogiou Belik Daria;
International symposium of the IRHT: CD34+ and other stem cell promises: key to pluripotent clinical applications? Talk given at a conference Cardiac progenitor cells: Are they superior or just different? 23.10.2017 Mulhouse, France Kuster Gabriela;
Department of Biomedicine PhD 5th Scientific Retreat Talk given at a conference The role of Plk2 in cardiomyocyte cell cycle and proliferation 18.05.2017 Quarten, Switzerland Monogiou Belik Daria;
ISSCR International Symposium 2017 Poster Downregulation of polo-like kinase 2 enhances lineage commitment and facilitates endothelial differentiation in different types of cardiac progenitor cells 27.02.2017 Basel, Switzerland Pfister Otmar; Lorenz Vera; Kuster Gabriela;
12th SSCN Annual Meeting Poster Matrix protein-instructed rapid regulation of yes-associated protein and polo-like kinase 2 are novel cues for the endothelial differentiation of cardiac progenitor cells 29.06.2016 Fribourg, Switzerland Pfister Otmar; Kuster Gabriela; Lorenz Vera;
Department of Biomedicine PhD 4th Scientific Retreat Poster Identification of the molecular signature of side population cardiac progenitor cells and of strategies for regenerative potential enhancement. 26.05.2016 Emmetten, Switzerland Monogiou Belik Daria;
Cardiovascular and Metabolic Research Conference (5th joint meeting of the SSC working groups AGLA and CVBG) Talk given at a conference Flt3 signaling is important for cardiac vasculogenesis and function 14.01.2016 Fribourg, Switzerland Pfister Otmar; Kuster Gabriela; Lorenz Vera;
Cardiovascular and Metabolic Research Conference (5th joint meeting of the SSC working groups AGLA and CVBG) Talk given at a conference Rapid regulation of yes-associated protein and polo-like kinase 2 are early steps in extracellular matrix protein-instructed cardiac progenitor cell fate 14.01.2016 Fribourg, Switzerland Kuster Gabriela; Pfister Otmar; Lorenz Vera;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Tag der Biomedizin, Departement Biomedizin, Universitätsspital und Universität Basel German-speaking Switzerland 2016

Associated projects

Number Title Start Funding scheme
189877 Lnc-ing Cancer Drugs to Cardiotoxicity: Contribution of lncRNAs to Tyrosine Kinase Inhibitor-Related Cardiac Side Effects 01.06.2020 COST (European Cooperation in Science and Technology)

Abstract

Increased apoptosis and premature senescence of cardiac progenitor cells (CPCs) result in impaired cardiac adaptation and enhanced susceptibility of anthracycline-exposed hearts to stressors. This may apply to targeted cancer drugs as well, given their targets are expressed in the heart and involved in the regulation of cardiac homeostasis. Fms-like tyrosine kinase 3 (Flt3) is an important drug target for solid tumor and acute myeloid leukemia treatment. We recently demonstrated that Flt3 is expressed on cardiomyocytes and CPCs, and that its activation protects against apoptosis and improves post-myocardial infarction remodeling and function in mice. Further preliminary data support the hypothesis that Flt3-signaling participates in the regulation of CPCs. In this study, we will test the hypothesis that disruption of Flt3-signaling disturbs CPC homeostasis and function and facilitates cardiac disease. We will (i) characterize the role and mechanisms of Flt3-signaling in the maintenance of the cardiac cellular homeostasis and determine the functional consequences of its disruption in the mouse heart, (ii) identify roles and molecular mechanisms of Flt3 signaling in the regulation of quiescence and in vitro proliferation and differentiation capacities of CPCs, and (iii) determine whether disruption of intrinsic Flt3 signaling facilitates cardiac disease in response to additional stressors.Relevance: Cardiomyopathy and heart failure are severe and potentially life-limiting side effects of cancer therapy. Improved understanding of the roles and molecular mechanisms of intrinsic Flt3-action in the heart is mandatory to anticipate potential cardiotoxic effects and to allow for early monitoring and interdisciplinary management of patients on Flt3-targeting therapy. Furthermore, the characterization of molecular targets of cancer therapy and their roles in the heart will help guide future cancer drug design and lead to the identification of novel therapeutic targets for the treatment of cardiomyopathy and heart failure in general.
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