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The Biological and Clinical Relevance of EVI1 Expression in Prostate Carcinogenesis

English title The Biological and Clinical Relevance of EVI1 Expression in Prostate Carcinogenesis
Applicant Lengerke Claudia
Number 164200
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Experimental Cancer Research
Start/End 01.09.2015 - 31.08.2018
Approved amount 150'000.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Cellular Biology, Cytology

Keywords (3)

prostate carcinoma; tumor stem cells; EVI1

Lay Summary (German)

Lead
Das Gen Ecotropic viral integration site 1 (EVI1) ist als negativer prognostischer Faktor bei akuten Leukämien und für seine Rolle in Blutstammzellen bekannt. Die Expression und Rolle von EVI1 in Prostatageweben ist weitgehend unbekannt. In Zusammenarbeit mit der Forschungsgruppe von Professor Sven Perner, Institut für Pathologie an der Universitätsklinik Bonn (seit 08/2015 Lübeck), konnten wir Expression von EVI1 in Prostatakarzinomen sowie in putativen Stammzellen der gesunder Prostata (sogenannten Basalzellen) nachweisen. Das jetzige Projekt untersucht die Bedeutung der EVI1 Expression als Stammzell- und Biomarker bei Prostatakarzinomen und seine funktionellen Rollen und molekulare Regulation in dieser Tumorentität.
Lay summary

Unsere Hypothese ist dass EVI1 Expression in Prostatakarzinomen Stammzellen reguliert, und dadurch für  umorentstehung, -aggressivität und -ausbreitung von Bedeutung ist.

Folgende Ziele werden verfolgt:

1) Es soll eine detaillierte Analyse der EVI1 Expression in drei etablierten Kohorten von Prostatakarzinom-Patienten durchgeführt werden. Die EVI1 Expressionshöhe wird in Zusammenhang mit bereits erhobenen klinischen Daten analysiert. Des Weiteren sollen Genrearrangements/-amplifikationen und -mutationen als Ursache für die beobachtete EVI1-Expression in diesen Patienten untersucht werden. 

2) Analyse der Ko-Expression von EVI1 mit anderen Stammzellmarkern (SOX2, ALDH1) in diesen Proben.

3) Generierung von EVI1 knockdown und Überexpressions-Prostatakarzinomzellen (unter Verwendung lentiviraler Vektoren) und Untersuchung der funktionellen Konsequenzen bezüglich Zellproliferation, -tod, -migration und Tumorentstehung. 

4) Etablierung eines Zebrafisch-Xenograftmodels für Prostatakarzinomen zur Untersuchung von Primärtumorzellen.

5) Molekulare Analysen zur Identifikation von EVI1-Zielgenen im Prostatakarzinom (Genexpression und Chromatinimmunpräziptation Analysen)

6) Untersuchung neuartiger (gegen EVI1 gerichteter) Therapien in Prostatakarzinomzellen (e.g. Arsen Trioxid).

Das Prostatakarzinom ist das häufigste Krebsleiden und derzeit die zweithäufigste Krebstodesursache des Mannes. EVI1 ist bisher im Prostatakarzinom weitgehend unstudiert, könnte hier jedoch wichtige Rollen als prognostischer Faktor sowie in der Tumorentstehung/-ausbreitung spielen. EVI1 Inhibitoren könnten ein Bestandteil der Behandlung von Prostatakarzinomen werden.

 

Direct link to Lay Summary Last update: 24.08.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Cancer Stem Cells
Wang Hui, Paczulla Anna M., Konantz Martina, Lengerke Claudia (2018), Cancer Stem Cells, Springer New York, New York, NY, 77-87.
Prominent Oncogenic Roles of EVI1 in Breast Carcinoma
Wang Hui, Schaefer Thorsten, Konantz Martina, Braun Martin, Varga Zsuzsanna, Paczulla Anna M., Reich Selina, Jacob Francis, Perner Sven, Moch Holger, Fehm Tanja N., Kanz Lothar, Schulze-Osthoff Klaus, Lengerke Claudia (2017), Prominent Oncogenic Roles of EVI1 in Breast Carcinoma, in Cancer Research, 77(8), 2148-2160.
Ecotropic viral integration site 1, a novel oncogene in prostate cancer
Queisser A., Hagedorn S., Wang H., Schaefer T., Konantz M., Alavi S., Deng M., Vogel W., Von Mässenhausen A., Kristiansen G., Duensing S., Kirfel J., Lengerke C., Perner S. (2017), Ecotropic viral integration site 1, a novel oncogene in prostate cancer, in Oncogene, 36(11), 1573-1584.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Klaus Schulz-Osthoff, University of Tübingen, Department of Biochemistry, Germany Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Lothar Kanz, University Hospital Tübingen, Medical Clinic II Germany (Europe)
- Publication
Tanja N. Fehm, Department of Gynecology and Obstetrics, University Hospital Duesseldorf Germany (Europe)
- Publication
Holger Moch, Pathology and Molecular Pathology, University Hospital Zurich, Zurich Switzerland (Europe)
- Publication
Zsuzsanna Varga, Pathology and Molecular Pathology, University Hospital Zurich Switzerland (Europe)
- Publication
Prof. Dr. Sven Perner, University of Bonn, Department of Pathology Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Francis Jacob, Departement für Biomedizin, Universitätsspital Basel, Ovarian Cancer Research Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Jahrestagung der Deutschen Gesellschaft für Hämatologie und Onkologie Talk given at a conference EVI1-a novel oncogene in prostate carcinoma 14.10.2016 Leibzig, Germany Perner Sven; Schäfer Thorsten; Lengerke Claudia;
Jahrestagung der Deutschen Gesellschaft für Hämatologie und Onkologie Talk given at a conference Novel oncogenic roles of the transcriptional regulator EVI1 in ER-breast carcinoma 14.10.2016 Leibzig, Germany Perner Sven; Schäfer Thorsten; Lengerke Claudia;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Joint MD-PhD/MSc Retreat 2017 Talk 09.11.2017 Rigi, Switzerland Lengerke Claudia;
Career path translational scientist in academic medicine Workshop 25.03.2017 Thun, Switzerland Lengerke Claudia;
Sommerakademie der Stiftung des Deutschen Volkes Workshop 20.09.2015 Nizza, France Perner Sven; Lengerke Claudia;


Abstract

Cancer stem cells (CSCs) are considered essential regulators of tumor initiation, pro-gression and therapy resistance. Previous work from our and other labs indicate that the embryonic stem cell protein SOX2 is a CSC marker in ovarian, breast and prostate carci-noma (PCa), and furthermore plays oncogenic roles in lung and different types of squamous carcinomas. In this proposal, we plan to expand our knowledge on the regula-tion of PCa CSC by investigating the transcriptional stem cell regulator Ecotropic viral in-tegration site 1 (EVI1). EVI1 has been mainly studied in acute myeloid leukemia (AML) where high EVI1 expression indicates particularly adverse clinical outcome. EVI1 is known to express in healthy hematopoietic stem cells and discussed as a leukemia CSC marker. Even though EVI1 is expressed in PCa, almost no data exists on ist role in this tumor entity. Preliminary data from our labs suggest that EVI1 is a stem cell marker in prostate tissues and enhances disease aggressiveness of PCa. Here, we propose to analyze expression, roles and molecular targets of EVI1 in PCa with particular focus on its relationship to PCa CSCs. EVI1 protein expression will be analyzed in four indepen-dent PCa patient cohorts consisting either of primary tumors, localized lymph node and hormone-refractory distant metastases or only of primary tumors, and investigated as a potential biomarker and predictor of adverse prognosis in PCa. Next, we will analyze whether amplification, translocation or activating mutations associate with EVI1 protein overexpression in PCa patient samples and cell lines. Using a lentiviral reporter system for the SOX2 regulatory regions 1 and 2 available in our lab and previously published as-says, the association between EVI1 expression and established PCa stem cell markers will be explored. Potential functions mediated by EVI1 expression in PCa cells (including maintenance of PCa stem cell identity, growth, proliferation, apoptosis resistance, migra-tion, invasion and in vivo tumorigenicity) will be investigated using human PCa cells with modified EVI1 expression generated using lentiviral constructs. In vivo tumorigenicity as-says will be performed in established NSG mouse xenograft assays and a newly develo-ped zebrafish xenograft model. RNA-Seq and ChIP analyses will be performed on PCa cells to identify drugable molecular targets of EVI1. Previously reported relevant target pathways (e.g. Smad3/TGF-beta, BCL proteins) and arsenic trioxide (ATO), which has recently been reported to inhibit EVI1 protein stability in leukemic cells, will be explored for their efficacy to antagonize EVI1-dependent oncogenic effects in PCa cells in vitro and eventually also in vivo. The data emerging from this project will improve our under-standing of the molecular pathogenesis in PCa and may contribute to the development of personalized treatments for PCa patients.
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