title: Tbx3 fosters pancreatic cancer growth by increased angiogenesis and activin/nodal-dependent induction of stemness.
abstract: Cell fate decisions and pluripotency, but also malignancy depend on networks of key transcriptional regulators. The T-box transcription factor TBX3 has been implicated in the regulation of embryonic stem cell self-renewal and cardiogenesis. We have recently discovered that forced TBX3 expression in embryonic stem cells promotes mesendoderm specification directly by activating key lineage specification factors and indirectly by enhancing paracrine NODAL signalling. Interestingly, aberrant TBX3 expression is associated with breast cancer and melanoma formation. In other cancers, loss of TBX3 expression is associated with a more aggressive phenotype e.g. in gastric and cervical cancer. The precise function of TBX3 in pancreatic ductal adenocarcinoma remains to be determined. In the current study we provide conclusive evidence for TBX3 overexpression in pancreatic cancer samples as compared to healthy tissue. While proliferation remains unaltered, forced TBX3 expression strongly increases migration and invasion, but also angiogenesis in vitro and in vivo. Finally, we describe the TBX3-dependency of cancer stem cells that perpetuate themselves through an autocrine TBX3-ACTIVIN/NODAL signalling loop to sustain stemness. Thus, TBX3 is a new key player among pluripotency-related genes driving cancer formation.
authors.affiliation: Department of Internal Medicine I, Ulm University, Ulm, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Perkhofer
authors.affiliation: Department of Internal Medicine I, Ulm University, Ulm, Germany.
authors.forename: Karolin
authors.initials: K
authors.lastname: Walter
authors.affiliation: IZKF Computational Biology Research Group, Medical Faculty, RWTH University Aachen, Germany.
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Costa
authors.affiliation: Department of Internal Medicine I, Ulm University, Ulm, Germany.
authors.forename: Maria C Romero
authors.initials: MC
authors.lastname: Carrasco
authors.affiliation: Department of Internal Medicine I, Ulm University, Ulm, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Eiseler
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hafner
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Genze
authors.affiliation: Department of Cell Biology, Institute for Biomedical Engineering, Medical Faculty, RWTH University Aachen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenke
authors.affiliation: Department of Internal Medicine I, Ulm University, Ulm, Germany.
authors.forename: Wendy
authors.initials: W
authors.lastname: Bergmann
authors.affiliation: Department of Internal Medicine I, Ulm University, Ulm, Germany.
authors.forename: Anett
authors.initials: A
authors.lastname: Illing
authors.affiliation: Department of Internal Medicine I, Ulm University, Ulm, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Hohwieler
authors.affiliation: Department of Internal Medicine I, Ulm University, Ulm, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhntop
authors.affiliation: Department of Cell Biology, Institute for Biomedical Engineering, Medical Faculty, RWTH University Aachen, Germany.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Core Facility Genomics, Medical Faculty, Ulm University, Ulm, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Holzmann
authors.affiliation: Department of Internal Medicine I, Ulm University, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
authors.affiliation: Department of Internal Medicine I, Ulm University, Ulm, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Institute of Neuroanatomy, Eberhard Karls University Tuebingen, Tuebingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebau
authors.affiliation: Department of Internal Medicine I, Ulm University, Ulm, Germany. Electronic address: patrick.hermann@uni-ulm.de.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Hermann
authors.affiliation: Department of Internal Medicine I, Ulm University, Ulm, Germany. Electronic address: alexander.kleger@uni-ulm.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kleger
authors.affiliation: Department of Internal Medicine I, Ulm University, Ulm, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Müller
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism; D028341:Activins / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism; D009389:Neovascularization, Pathologic; D055457:Nodal Protein / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D018874:Spheroids, Cellular / Q000166:cytology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071916:AC133 Antigen; D055457:Nodal Protein; D020825:T-Box Domain Proteins; C106884:TBX3 protein, human; D028341:Activins
keywords: Cancer stem cells; Development; Pancreas; Pancreatic adenocarcinoma; TBX3