title: Membranous CD24 drives the epithelial phenotype of pancreatic cancer.
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.
authors.affiliation: II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Lubeseder-Martellato
authors.affiliation: II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Hidalgo-Sastre
authors.affiliation: II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.|Current address: Klinik für Anaesthesiologie, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Alexandrow
authors.affiliation: II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Kamyabi-Moghaddam
authors.affiliation: Institute of Pathology, University Tübingen, Tübingen, Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wirth
authors.affiliation: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Neff
authors.affiliation: II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.|Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Reichert
authors.affiliation: Institute of Radiology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Heid
authors.affiliation: II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Institute of Radiology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Rickmer
authors.initials: R
authors.lastname: Braren
authors.affiliation: II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
mesh_terms: D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D002108:Ceruletide / Q000737:chemistry; D058750:Epithelial-Mesenchymal Transition; D004848:Epithelium / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010195:Pancreatitis / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D015854:Up-Regulation
chemical_list: D051927:CD24 Antigen; C497889:CD24 protein, human; C497890:Cd24a protein, mouse; D002108:Ceruletide; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: CD24; EMT; MET; pancreatic ductal adenocarcinoma; β-catenin