title: Role of CCL20 mediated immune cell recruitment in NF-κB mediated TRAIL resistance of pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers. From a clinical view, the transcription factor NF-κB is of particular importance, since this pathway confers apoptosis resistance and limits drug efficacy. Whereas the role of the most abundant NF-κB subunit p65/RelA in therapeutic resistance is well documented, only little knowledge of the RelA downstream targets and their functional relevance in TRAIL mediated apoptosis in PDAC is available. In the present study TRAIL resistant and sensitive PDAC cell lines were analyzed for differentially expressed RelA target genes, to define RelA downstream targets mediating TRAIL resistance. The most upregulated target gene was then further functionally characterized. Unbiased genome-wide expression analysis demonstrated that the chemokine CCL20 represents the strongest TRAIL inducible direct RelA target gene in resistant PDAC cells. Unexpectedly, targeting CCL20 by siRNA, blocking antibodies or by downregulation of the sole CCL20 receptor CCR6 had no effect on PDAC cell death or cancer cell migration, arguing against an autocrine role of CCL20 in PDAC. However, by using an ex vivo indirect co-culture system we were able to show that CCL20 acts paracrine to recruit immune cells. Importantly, CCL20-recruited immune cells further increase TRAIL resistance of CCL20-producing PDAC cells. In conclusion, our data show a functional role of a RelA-CCL20 pathway in PDAC TRAIL resistance. We demonstrate how the therapy-induced cross-talk of cancer cells with immune cells affects treatment responses, knowledge needed to tailor novel bi-specific treatments, which target tumor cell as well as immune cells.
authors.affiliation: Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Geismann
authors.affiliation: Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Grohmann
authors.affiliation: Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Dreher
authors.affiliation: Institute of Clinical Molecular Biology, UKSH Campus Kiel, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Häsler
authors.affiliation: Institute of Clinical Molecular Biology, UKSH Campus Kiel, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, UKSH Campus Kiel, Kiel, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Legler
authors.affiliation: Department of Surgery, UKSH Campus Kiel, Kiel, German.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hauser
authors.affiliation: Department of Surgery, UKSH Campus Kiel, Kiel, German.
authors.forename: Jan Hendrik
authors.initials: JH
authors.lastname: Egberts
authors.affiliation: Institute of Pathology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany; Institute of Clinical Molecular Biology, UKSH Campus Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Clinic for Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Linkermann
authors.affiliation: Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, Munich, Germany.
authors.forename: Zonera
authors.initials: Z
authors.lastname: Hassan
authors.affiliation: Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, Munich, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany; Institute of Experimental Cancer Research, UKSH Campus Kiel, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Schäfer
authors.affiliation: Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany. Electronic address: aarlt@1med.uni-kiel.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Arlt
mesh_terms: D000328:Adult; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*
chemical_list: C108355:CCL20 protein, human; D054418:Chemokine CCL20; D016328:NF-kappa B; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand
keywords: Apoptosis resistance; CCL20; NF-κB; Pancreatic cancer; TRAIL