Z Gastroenterol 2017; 55(08): e57-e299
DOI: 10.1055/s-0037-1604920
Kurzvorträge
Pankreas
Mechanismen der Pankreaskarzinomentstehung: Donnerstag, 14 September 2017, 08:00 – 09:20, Coventry/Forschungsforum 4
Georg Thieme Verlag KG Stuttgart · New York

Bcl-3 deficiency promotes cancer stem cell-ness and metastatic properties in pancreatic ductal adenocarcinoma

SM Wörmann
1   Klinikum rechts der Isar der Technischen Universität München, Klinik und Poliklinik für Innere Medizin II, München, Deutschland
,
J Ai
1   Klinikum rechts der Isar der Technischen Universität München, Klinik und Poliklinik für Innere Medizin II, München, Deutschland
,
M Vallespinos
2   Department of Biochemistry, Autónoma University of Madrid, School of Medicine, Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, Madrid, Spanien
,
KN Diakopoulos
1   Klinikum rechts der Isar der Technischen Universität München, Klinik und Poliklinik für Innere Medizin II, München, Deutschland
,
K Steiger
3   Technische Universität München, Institute for Pathology, München, Deutschland
,
J Slotta-Huspenina
3   Technische Universität München, Institute for Pathology, München, Deutschland
,
M Riemann
4   Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Deutschland
,
B Sainz
2   Department of Biochemistry, Autónoma University of Madrid, School of Medicine, Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, Madrid, Spanien
,
H Algül
1   Klinikum rechts der Isar der Technischen Universität München, Klinik und Poliklinik für Innere Medizin II, München, Deutschland
,
M Lesina
1   Klinikum rechts der Isar der Technischen Universität München, Klinik und Poliklinik für Innere Medizin II, München, Deutschland
› Author Affiliations
Further Information

Publication History

Publication Date:
02 August 2017 (online)

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Introduction:

For the majority of patients with pancreatic ductal adenocarcinoma (PDAC), the high metastatic capacity is life limiting. Mechanisms regulating metastatic capacities are not fully understood. B-cell CLL/lymphoma 3 (Bcl-3), an atypical member of the ankyrin repeat-containing IκB family of NF-κB inhibitors, is an established oncogene in chronic lymphocytic leukemia. In addition to its implication in haematological malignancies, emerging evidence indicates that Bcl-3 is also important in solid tumor formation and growth. In this study, we aimed to determine the role of Bcl-3 in pancreatic cancer for the first time.

Material and methods:

PDAC tissues and cell lines obtained from humans and a KrasG12D mouse model (KC) of pancreatic cancer were investigated for Bcl-3 expression. The overall survival of human PDACs expressing high and low levels of Bcl-3 was compared. Further, Bcl-3 was deleted in a Kras G12D mouse model with pancreas-specific inactivation of p53 (KCPB) and tumor incidence, metastases as well as proliferation, and apoptosis in tumor tissues and primary tumor cells of KCP and KCPB mice were investigated.

Results:

Using genetic tools we provide evidence that Bcl-3 is expressed in both human and murine PDAC, and loss of Bcl-3 significantly impacts tumor burden by accelerating tumorigenesis, proliferation and curtailing overall survival. Bcl-3 expression influences tumor differentiation and averts an epithelial to mesenchymal transition. In addition, deletion of Bcl-3 in tumor cells resulted in metabolic alterations promoting oxidative metabolism and expansion of the cancer stem cells (CSC) compartment, leading to more aggressive and metastatic tumors. These observations were replicated in established PDAC cell lines and human tissues.

Conclusions:

Here, we reveal Bcl-3 as a new tumor suppressor regulating key elements of metastasis in pancreatic ductal adenocarcinoma. Our study indicates an important and previously unrecognized role for Bcl-3 in PDAC and highlights several new aspects of Bcl-3 in this disease.