Jiaoyu Ai1, Sonja M Wörmann2, Kıvanç Görgülü1, Mireia Vallespinos3, Sladjana Zagorac4, Sonia Alcala3, Nan Wu1, Derya Kabacaoglu1, Alexandra Berninger1, Diego Navarro3, Ezgi Kaya-Aksoy1, Dietrich A Ruess5, Katrin J Ciecielski1, Marlena Kowalska1, Ekin I Demir6, Güralp O Ceyhan6, Irina Heid7, Rickmer Braren7, Marc Riemann8, Sabrina Schreiner9, Samuel Hofmann9, Maria Kutschke10, Martin Jastroch10, Julia Slotta-Huspenina11, Alexander Muckenhuber11, Anna Melissa Schlitter12, Roland M Schmid1, Katja Steiger12, Kalliope N Diakopoulos1, Marina Lesina1, Bruno Sainz13, Hana Algül14. 1. Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, Munich, Germany. 2. Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Ahmed Cancer Center for Pancreatic Cancer Research, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA. 3. Department of Biochemistry, Autónoma University of Madrid, School of Medicine, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain; Enfermedades Crónicas y Cáncer Area, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain. 4. Department of Biochemistry, Autónoma University of Madrid, School of Medicine, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain; Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, United Kingdom. 5. Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Department of General and Visceral Surgery, Center for Surgery, Medical Center, University of Freiburg, Freiburg, Germany. 6. Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. 7. Institute for Diagnostic and Interventional Radiology, Klinikum rechts der Isar der, Technische Universität München, Munich, Germany. 8. Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany. 9. Institute for Virology, Technical University of Munich, Neuherberg, Germany. 10. Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Garching, Germany. 11. Institute for Pathology, Technische Universität München, Munich, Germany; MTBio-Biobank of Technische Universität München and University Hospital Klinikum rechts der Isar, Munich, Germany. 12. Institute for Pathology, Technische Universität München, Munich, Germany. 13. Department of Biochemistry, Autónoma University of Madrid, School of Medicine, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain; Enfermedades Crónicas y Cáncer Area, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain. Electronic address: bsainz@iib.uam.es. 14. Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, Munich, Germany. Electronic address: hana.alguel@mri.tum.de.
Abstract
BACKGROUND & AIMS: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown. METHODS: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing in vivo and in vitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes. RESULTS: Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes. CONCLUSIONS: We demonstrate that bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches.
BACKGROUND & AIMS: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown. METHODS: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing in vivo and in vitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes. RESULTS:Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes. CONCLUSIONS: We demonstrate that bcl3impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches.
Authors: Sonja M Wörmann; Amy Zhang; Fredrik I Thege; Robert W Cowan; Dhwani N Rupani; Runsheng Wang; Sara L Manning; Chris Gates; Weisheng Wu; Rena Levin-Klein; Kimal I Rajapakshe; Meifang Yu; Asha S Multani; Ya'an Kang; Cullen M Taniguchi; Katharina Schlacher; Melena D Bellin; Matthew H G Katz; Michael P Kim; Jason B Fleming; Steven Gallinger; Ravikanth Maddipati; Reuben S Harris; Faiyaz Notta; Susan R Ross; Anirban Maitra; Andrew D Rhim Journal: Nat Cancer Date: 2021-11-18
Authors: Fredrik I Thege; Dhwani N Rupani; Bhargavi Brahmendra Barathi; Sara L Manning; Anirban Maitra; Andrew D Rhim; Sonja M Wörmann Journal: Cancer Res Date: 2022-08-03 Impact factor: 13.312