Oncotarget

Research Papers:

Membranous CD24 drives the epithelial phenotype of pancreatic cancer

Clara Lubeseder-Martellato _, Ana Hidalgo-Sastre, Carolin Hartmann, Katharina Alexandrow, Zahra Kamyabi-Moghaddam, Bence Sipos, Matthias Wirth, Florian Neff, Maximilian Reichert, Irina Heid, Günter Schneider, Rickmer Braren, Roland M. Schmid, Jens T. Siveke

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Oncotarget. 2016; 7:49156-49168. https://doi.org/10.18632/oncotarget.9402

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Abstract

Clara Lubeseder-Martellato1, Ana Hidalgo-Sastre1, Carolin Hartmann1,4, Katharina Alexandrow1, Zahra Kamyabi-Moghaddam1, Bence Sipos3, Matthias Wirth1, Florian Neff5, Maximilian Reichert1,6, Irina Heid2, Günter Schneider1, Rickmer Braren2, Roland M. Schmid1,5, Jens T. Siveke1,5,7

1II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany

2Institute of Radiology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany

3Institute of Pathology, University Tübingen, Tübingen, Germany

4Current address: Klinik für Anaesthesiologie, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany

5German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

6Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

7Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany

Correspondence to:

Clara Lubeseder-Martellato, email: clara.lubeseder-martellato@tum.de

Jens T. Siveke, email: j.siveke@dkfz.de

Keywords: CD24, pancreatic ductal adenocarcinoma, β-catenin, MET, EMT

Received: July 31, 2015    Accepted: April 22, 2016    Published: May 17, 2016

ABSTRACT

Surface CD24 has previously been described, together with CD44 and ESA, for the characterization of putative cancer stem cells in pancreatic ductal adenocarcinoma (PDAC), the most fatal of all solid tumors. CD24 has a variety of biological functions including the regulation of invasiveness and cell proliferation, depending on the tumor entity and subcellular localization. Genetically engineered mouse models (GEMM) expressing oncogenic KrasG12D recapitulate the human disease and develop PDAC. In this study we investigate the function of CD24 using GEMM of endogenous PDAC and a model of cerulein-induced acute pancreatitis. We found that (i) CD24 expression was upregulated in murine and human PDAC and during acute pancreatitis (ii) CD24 was expressed exclusively in differentiated PDAC, whereas CD24 absence was associated with undifferentiated tumors and (iii) membranous CD24 expression determines tumor subpopulations with an epithelial phenotype in grafted models. In addition, we show that CD24 protein is stabilized in response to WNT activation and that overexpression of CD24 in pancreatic cancer cells upregulated β-catenin expression augmenting an epithelial, non-metastatic signature. Our results support a positive feedback model according to which (i) WNT activation and subsequent β-catenin dephosphorylation stabilize CD24 protein expression, and (ii) sustained CD24 expression upregulates β-catenin expression. Eventually, membranous CD24 augments the epithelial phenotype of pancreatic tumors. Thus we link the WNT/β-catenin pathway with the regulation of CD24 in the context of PDAC differentiation.


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