Wang Hui, Paczulla Anna M., Konantz Martina, Lengerke Claudia (2018), Cancer Stem Cells, Springer New York, New York, NY, 77-87.
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.
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.
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.