title: Transcriptional co-factor Transducin beta-like (TBL) 1 acts as a checkpoint in pancreatic cancer malignancy.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer fatalities in Western societies, characterized by high metastatic potential and resistance to chemotherapy. Critical molecular mechanisms of these phenotypical features still remain unknown, thus hampering the development of effective prognostic and therapeutic measures in PDAC. Here, we show that transcriptional co-factor Transducin beta-like (TBL) 1 was over-expressed in both human and murine PDAC. Inactivation of TBL1 in human and mouse pancreatic cancer cells reduced cellular proliferation and invasiveness, correlating with diminished glucose uptake, glycolytic flux, and oncogenic PI3 kinase signaling which in turn could rescue TBL1 deficiency-dependent phenotypes. TBL1 deficiency both prevented and reversed pancreatic tumor growth, mediated transcriptional PI3 kinase inhibition, and increased chemosensitivity of PDAC cells in vivo. As TBL1 mRNA levels were also found to correlate with PI3 kinase levels and overall survival in a cohort of human PDAC patients, TBL1 was identified as a checkpoint in the malignant behavior of pancreatic cancer and its expression may serve as a novel molecular target in the treatment of human PDAC.
authors.affiliation: Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Stoy
authors.affiliation: Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Aishwarya
authors.initials: A
authors.lastname: Sundaram
authors.affiliation: Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Marcos
authors.initials: M
authors.lastname: Rios Garcia
authors.affiliation: Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Wang
authors.affiliation: Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Oksana
authors.initials: O
authors.lastname: Seibert
authors.affiliation: Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany Institute for Diabetes and Cancer IDC Helmholtz Center Munich and Joint Heidelberg-IDC Translational Diabetes Program, Neuherberg, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Zota
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Wendler
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Männle
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Hinz
authors.affiliation: Medical Research Center, Klinikum Mannheim, Mannheim, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.affiliation: Medical Research Center, Klinikum Mannheim, Mannheim, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Muciek
authors.affiliation: Medical Research Center, Klinikum Mannheim, Mannheim, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.affiliation: Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Rose
authors.affiliation: Research Group Cellular Senescence, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Greiner
authors.affiliation: Research Group Cellular Senescence, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hofmann
authors.affiliation: Functional Genome Analysis, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bauer
authors.affiliation: Functional Genome Analysis, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hoheisel
authors.affiliation: Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany Institute for Diabetes and Cancer IDC Helmholtz Center Munich and Joint Heidelberg-IDC Translational Diabetes Program, Neuherberg, Germany.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Berriel Diaz
authors.affiliation: Institute of Pathology Heidelberg University, Heidelberg, Germany.
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Gaida
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Werner
authors.affiliation: Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany Institute for Diabetes and Cancer IDC Helmholtz Center Munich and Joint Heidelberg-IDC Translational Diabetes Program, Neuherberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schafmeier
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany Oliver.Strobel@med.uni-heidelberg.de s.herzig@dkfz.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Strobel
authors.affiliation: Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany Institute for Diabetes and Cancer IDC Helmholtz Center Munich and Joint Heidelberg-IDC Translational Diabetes Program, Neuherberg, Germany Oliver.Strobel@med.uni-heidelberg.de s.herzig@dkfz.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Herzig
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000473:pathology*; D016019:Survival Analysis; D015293:Transducin / Q000172:deficiency / Q000378:metabolism*
chemical_list: C119542:TBL1X protein, human; C485613:Tbl1x protein, mouse; D015293:Transducin
keywords: PI3 kinase; TBL1; gemcitabine; pancreatic cancer; tumor metabolism