Wegwitz, Florian

[["dc.bibliographiccitation.firstpage","E521"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","International Journal of Cancer"],["dc.bibliographiccitation.lastpage","E533"],["dc.bibliographiccitation.volume","136"],["dc.contributor.author","Lenfert, Eva"],["dc.contributor.author","Maenz, Claudia"],["dc.contributor.author","Heinlein, Christina"],["dc.contributor.author","Jannasch, Katharina"],["dc.contributor.author","Schumacher, Udo"],["dc.contributor.author","Pantel, Klaus"],["dc.contributor.author","Tolstonog, Genrich V."],["dc.contributor.author","Deppert, Wolfgang R."],["dc.contributor.author","Wegwitz, Florian"],["dc.date.accessioned","2018-11-07T09:59:40Z"],["dc.date.available","2018-11-07T09:59:40Z"],["dc.date.issued","2015"],["dc.description.abstract","To study the postulated mutant p53 (mutp53) gain of function effects in mammary tumor development, progression and metastasis, we crossed SV40 transgenic WAP-T mice with mutant p53 transgenic WAP-mutp53 mice. Compared to tumors in monotransgenic WAP-T mice, tumors in bitransgenic WAP-T x WAP-mutp53 mice showed higher tumor grading, enhanced vascularization, and significantly increased metastasis. Bitransgenic tumors revealed a gene signature associated with the oncogenic epithelial-mesenchymal transition pathway (EMT gene signature). In cultures of WAP-T tumor-derived G-2 cancer cells, which are comprised of subpopulations displaying mesenchymal and epithelial phenotypes, this EMT gene signature was associated with the mesenchymal compartment. Furthermore, ectopic expression of mutp53 in G-2 cells sufficed to induce a strong EMT phenotype. In contrast to these in vitro effects, monotransgenic and bitransgenic tumors were phenotypically similar suggesting that in vivo the tumor cell phenotype might be under control of the tumor microenvironment. In support, orthotopic transplantation of G-2 cells as well as of G-2 cells expressing ectopic mutp53 into syngeneic mice resulted in tumors with a predominantly epithelial phenotype, closely similar to that of endogenous primary tumors. We conclude that induction of an EMT gene signature by mutp53 in bitransgenic tumors primarily promotes tumor cell plasticity, that is, the probability of tumor cells to undergo EMT processes under appropriate stimuli, thereby possibly increasing their potential to disseminate and metastasize. What's new? Despite the loss of transcriptional activity, mutant p53 (mutp53) proteins display gain of function properties, such as the ability to contribute to tumor progression. To elucidate functional gains, the present study explored the effects of mutp53 expression in monotransgenic WAP-T mice and bitransgenic WAP-T x WAP-mutp53 mice. Mammary tumors from both models were phenotypically similar and possessed an epithelial-mesenchymal transition (EMT) gene signature associated with tumor cell plasticity. However, mammary tumors in bitransgenic mice showed enhanced metastatic potential. Additional findings from in vitro experiments indicate that the tumor microenvironment plays a key role in regulating tumor cell phenotype and invasiveness."],["dc.identifier.doi","10.1002/ijc.29186"],["dc.identifier.isi","000347705200005"],["dc.identifier.pmid","25195563"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/37647"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Wiley-blackwell"],["dc.relation.issn","1097-0215"],["dc.relation.issn","0020-7136"],["dc.title","Mutant p53 promotes epithelial-mesenchymal plasticity and enhances metastasis in mammary carcinomas of WAP-T mice"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","4275"],["dc.bibliographiccitation.issue","41"],["dc.bibliographiccitation.journal","Oncogene"],["dc.bibliographiccitation.lastpage","4288"],["dc.bibliographiccitation.volume","30"],["dc.contributor.author","Gerstel, Daniela"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Jannasch, Katharina"],["dc.contributor.author","Ludewig, P."],["dc.contributor.author","Scheike, K."],["dc.contributor.author","Alves, Frauke"],["dc.contributor.author","Beauchemin, Nicole"],["dc.contributor.author","Deppert, Wolfgang R."],["dc.contributor.author","Wagener, Christoph"],["dc.contributor.author","Horst, Andrea Kristina"],["dc.date.accessioned","2018-11-07T08:51:04Z"],["dc.date.available","2018-11-07T08:51:04Z"],["dc.date.issued","2011"],["dc.description.abstract","We have studied the effects of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) on tumor angiogenesis in murine ductal mammary adenocarcinomas. We crossed transgenic mice with whey acidic protein promoter-driven large T-antigen expression (WAP-T mice) with oncogene-induced mammary carcinogenesis with CEA-CAM1null mice, and with Tie2-Ceacam1 transgenics, in which the Tie2 promoter drives endothelial overexpression of CEACAM1 (WAP-T x CEACAM1(endo+) mice), and analyzed tumor vascularization, angiogenesis and vessel maturation in these mice. Using flat-panel volume computed tomography (fpVCT) and histology, we found that WAP-T x CEACAM1(endo+) mice exhibited enhanced tumoral vascularization owing to CEACAM1(+) vessels in the tumor periphery, and increased intratumoral angiogenesis compared with controls. In contrast, vascularization of CEACAM1null/WAP-T-derived tumors was poor, and tumor vessels were dilated, leaky and showed poor pericyte coverage. Consequently, the tumoral vasculature could not be visualized in CEACAM1null/WAP-T mice by fpVCT, and we observed poor organization of the perivascular extracellular matrix (ECM), accompanied by the accumulation of collagen IV-degrading matrix metalloproteinase 9(+) (MMP9(+)) leukocytes and stromal cells. Vascular instability and alterations in ECM structure were accompanied by a significant increase in pulmonary metastases in CEACAM1null/WAP-T mice, whereas only occasional metastases were observed in CEACAM1(+) hosts. In CEACAM1(+) hosts, intratumoral vessels did not express CEACAM1, but they were intact, extensively covered with pericytes and framed by a well-organized perivascular ECM. MMP9(+) accessory cells were largely absent. Orthotopic transplantation of primary WAP-T- and CEACAM1null/WAP-T tumors into all three mouse lines confirmed that a CEACAM1(+) host environment is a prerequisite for productive angiogenic remodeling of the tumor microenvironment. Hence, CEACAM1 expression in the tumor periphery determines the vascular phenotype in a tumor, whereas systemic absence of CEACAM1 interferes with the formation of an organized tumor matrix and intratumoral vessel maturation. Oncogene (2011) 30, 4275-4288; doi: 10.1038/onc.2011.146; published online 2 May 2011"],["dc.description.sponsorship","German Research Foundation [SPP1190]"],["dc.identifier.doi","10.1038/onc.2011.146"],["dc.identifier.isi","000296356300005"],["dc.identifier.pmid","21532628"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/21845"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","0950-9232"],["dc.title","CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","25"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","International Journal of Cancer"],["dc.bibliographiccitation.lastpage","36"],["dc.bibliographiccitation.volume","137"],["dc.contributor.author","Jannasch, Katharina"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Lenfert, Eva"],["dc.contributor.author","Maenz, Claudia"],["dc.contributor.author","Deppert, Wolfgang R."],["dc.contributor.author","Alves, Frauke"],["dc.date.accessioned","2018-11-07T09:55:37Z"],["dc.date.available","2018-11-07T09:55:37Z"],["dc.date.issued","2015"],["dc.description.abstract","In this study, the effects of the standard chemotherapy, cyclophosphamide/adriamycin/5-fluorouracil (CAF) on tumor growth, dissemination and recurrence after orthotopic implantation of murine G-2 cells were analyzed in the syngeneic immunocompetent whey acidic protein-T mouse model (Wegwitz et al., PLoS One 2010; 5:e12103; Schulze-Garg et al., Oncogene 2000; 19:1028-37). Single-dose CAF treatment reduced tumor size significantly, but was not able to eradicate all tumor cells, as recurrent tumor growth was observed 4 weeks after CAF treatment. Nine days after CAF treatment, residual tumors showed features of regressive alterations and were composed of mesenchymal-like tumor cells, infiltrating immune cells and some tumor-associated fibroblasts with an intense deposition of collagen. Recurrent tumors were characterized by coagulative necrosis and less tumor cell differentiation compared with untreated tumors, suggesting a more aggressive tumor phenotype. In support, tumor cell dissemination was strongly enhanced in mice that had developed recurrent tumors in comparison with untreated controls, although only few disseminated tumor cells could be detected in various organs 9 days after CAF application. In vitro experiments revealed that CAF treatment of G-2 cells eliminates the vast majority of epithelial tumor cells, whereas tumor cells with a mesenchymal phenotype survive. These results together with the in vivo findings suggest that tumor cells that underwent epithelial-mesenchymal transition and/or exhibit stem-cell-like properties are difficult to eliminate using one round of CAF chemotherapy. The model system described here provides a valuable tool for the characterization of the effects of chemotherapeutic regimens on recurrent tumor growth and on tumor cell dissemination, thereby enabling the development and preclinical evaluation of novel therapeutic strategies to target mammary carcinomas."],["dc.identifier.doi","10.1002/ijc.29369"],["dc.identifier.isi","000353297600003"],["dc.identifier.pmid","25449528"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/36792"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Wiley-blackwell"],["dc.relation.issn","1097-0215"],["dc.relation.issn","0020-7136"],["dc.title","Chemotherapy of WAP-T mouse mammary carcinomas aggravates tumor phenotype and enhances tumor cell dissemination"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","1118"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","Cell Death & Disease"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Mieczkowska, Iga K."],["dc.contributor.author","Pantelaiou-Prokaki, Garyfallia"],["dc.contributor.author","Prokakis, Evangelos"],["dc.contributor.author","Schmidt, Geske E."],["dc.contributor.author","Müller-Kirschbaum, Lukas C."],["dc.contributor.author","Werner, Marcel"],["dc.contributor.author","Sen, Madhobi"],["dc.contributor.author","Velychko, Taras"],["dc.contributor.author","Jannasch, Katharina"],["dc.contributor.author","Dullin, Christian"],["dc.contributor.author","Wegwitz, Florian"],["dc.date.accessioned","2022-01-11T14:05:43Z"],["dc.date.available","2022-01-11T14:05:43Z"],["dc.date.issued","2021"],["dc.description.abstract","Breast cancer (BC) is the most common cancer occurring in women but also rarely develops in men. Recent advances in early diagnosis and development of targeted therapies have greatly improved the survival rate of BC patients. However, the basal-like BC subtype (BLBC), largely overlapping with the triple-negative BC subtype (TNBC), lacks such drug targets and conventional cytotoxic chemotherapies often remain the only treatment option. Thus, the development of resistance to cytotoxic therapies has fatal consequences. To assess the involvement of epigenetic mechanisms and their therapeutic potential increasing cytotoxic drug efficiency, we combined high-throughput RNA- and ChIP-sequencing analyses in BLBC cells. Tumor cells surviving chemotherapy upregulated transcriptional programs of epithelial-to-mesenchymal transition (EMT) and stemness. To our surprise, the same cells showed a pronounced reduction of polycomb repressive complex 2 (PRC2) activity via downregulation of its subunits Ezh2 , Suz12, Rbbp7 and Mtf2 . Mechanistically, loss of PRC2 activity leads to the de-repression of a set of genes through an epigenetic switch from repressive H3K27me3 to activating H3K27ac mark at regulatory regions. We identified Nfatc1 as an upregulated gene upon loss of PRC2 activity and directly implicated in the transcriptional changes happening upon survival to chemotherapy. Blocking NFATc1 activation reduced epithelial-to-mesenchymal transition, aggressiveness, and therapy resistance of BLBC cells. Our data demonstrate a previously unknown function of PRC2 maintaining low Nfatc1 expression levels and thereby repressing aggressiveness and therapy resistance in BLBC."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2022"],["dc.identifier.doi","10.1038/s41419-021-04407-y"],["dc.identifier.pii","4407"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/97731"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-507"],["dc.relation.eissn","2041-4889"],["dc.rights","CC BY 4.0"],["dc.title","Decreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","62"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","International Journal of Cancer"],["dc.bibliographiccitation.lastpage","70"],["dc.bibliographiccitation.volume","125"],["dc.contributor.author","Jannasch, Katharina"],["dc.contributor.author","Dullin, Christian"],["dc.contributor.author","Heinlein, Christina"],["dc.contributor.author","Krepulat, Frauke"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Deppert, Wolfgang R."],["dc.contributor.author","Alves, Frauke"],["dc.date.accessioned","2018-11-07T08:28:11Z"],["dc.date.available","2018-11-07T08:28:11Z"],["dc.date.issued","2009"],["dc.description.abstract","Transgenic mouse models offer an excellent opportunity for studying the molecular basis of cancer development and progression. Here we applied flat-panel volume computed tomography (fpVCT) to monitor tumor progression as well as the development of tumor vasculature in vivo in a transgenic mouse model for oncogene-induced mammary carcinogenesis (WAP-T mice). WAP-T mice develop multiple mammary carcinomas on oncogene induction within 3 to 5 months. Following induction, 3-dimensional fpVCT data sets were obtained by serial single scans of entire mice in combination with iodine containing contrast agents and served as basis for precise measurements of tumor volumes. Thereby, we were able to depict tumors within the mammary glands at a very early stage of the development. Tumors of small sizes (0.001 cm(3)) were detected by fpVCT before being palpable or visible by inspection. The capability to determine early tumor onset combined with longitudinal noninvasive imaging identified diverse time points of tumor onset for each mammary carcinoma and different tumor growth kinetics for multiple breast carcinomas that developed in single mice. Furthermore, blood supply to the breast tumors, as well as blood vessels around and within the tumors, were clearly visible over time by fpVCT. Three-dimensional visualization of tumor vessels in high resolution was enhanced by the use of a novel blood pool contrast agent. Here, we demonstrate by longitudinal fpVCT imaging that mammary carcinomas develop at different time points in each WAP-T mouse, and thereafter show divergent growth rates and distinct vascularization patterns. (C) 2009 UICC"],["dc.identifier.doi","10.1002/ijc.24332"],["dc.identifier.isi","000266569200008"],["dc.identifier.pmid","19384954"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6325"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/16366"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Wiley-liss"],["dc.relation.issn","0020-7136"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Detection of different tumor growth kinetics in single transgenic mice with oncogene-induced mammary carcinomas by flat-panel volume computed tomography"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]