title: CD95 promotes metastatic spread via Sck in pancreatic ductal adenocarcinoma.
abstract: Cancer stem cells (CSCs) have been implicated in the initiation and maintenance of tumour growth as well as metastasis. Recent reports link stemness to epithelial-mesenchymal transition (EMT) in cancer. However, there is still little knowledge about the molecular markers of those events. In silico analysis of RNA profiles of 36 pancreatic ductal adenocarcinomas (PDAC) reveals an association of the expression of CD95 with EMT and stemness that was validated in CSCs isolated from PDAC surgical specimens. CD95 expression was also higher in metastatic pancreatic cells than in primary PDAC. Pharmacological inhibition of CD95 activity reduced PDAC growth and metastasis in CSC-derived xenografts and in a murine syngeneic model. On the mechanistic level, Sck was identified as a novel molecule indispensable for CD95's induction of cell cycle progression. This study uncovers CD95 as a marker of EMT and stemness in PDAC. It also addresses the molecular mechanism by which CD95 drives tumour growth and opens tantalizing therapeutic possibilities in PDAC.
authors.affiliation: Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Teodorczyk
authors.affiliation: Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kleber
authors.affiliation: Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Wollny
authors.affiliation: Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: J P
authors.initials: JP
authors.lastname: Sefrin
authors.affiliation: Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Aykut
authors.affiliation: Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Mateos
authors.affiliation: Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Herhaus
authors.affiliation: Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: I
authors.identifier: 0000000343481038
authors.initials: I
authors.lastname: Sancho-Martinez
authors.affiliation: Apogenix GmbH, Heidelberg, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Hill
authors.affiliation: Apogenix GmbH, Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Gieffers
authors.affiliation: Apogenix GmbH, Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Sykora
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Weichert
authors.affiliation: 1] Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany [2] Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH, Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Eisen
authors.affiliation: 1] Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany [2] Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH, Heidelberg, Germany [3] German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Trumpp
authors.affiliation: 1] Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany [2] Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH, Heidelberg, Germany.
authors.forename: M R
authors.identifier: 0000000196917574
authors.initials: MR
authors.lastname: Sprick
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Bergmann
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Welsch
authors.affiliation: Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Martin-Villalba
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000503:physiopathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D055765:Shc Signaling Adaptor Proteins / Q000502:physiology*; D015398:Signal Transduction; D000071426:Src Homology 2 Domain-Containing, Transforming Protein 2; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000502:physiology*
chemical_list: D014408:Biomarkers, Tumor; C491901:FAS protein, human; C099021:SHC2 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071426:Src Homology 2 Domain-Containing, Transforming Protein 2; D019014:fas Receptor