A feedback-loop between telomerase activity and stemness factors regulates PDAC stem cells

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract To date, it is still unclear how cancer stem cells (CSCs) regulate their stemness properties, and to what extent they share common features with normal stem cells. Telomerase regulation is a key factor in stem cell maintenance. In this study, we investigate how telomerase regulation affects cancer stem cell biology in pancreatic ductal adenocarcinoma (PDAC), and delineate the mechanisms by which telomerase activity and CSC properties are linked. Using primary patient-derived pancreatic cancer cells, we show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic TERT -knockdown or pharmacological inhibitor (BIBR1532) resulted in CSC marker depletion in vitro , and reduced tumorigenicity in vivo . Furthermore, we identify a positive feedback loop between stemness factors (KLF4, SOX2, OCT3/4, NANOG) and telomerase, which is essential for the self-renewal of pancreatic CSCs. Disruption the balance between telomerase activity and stemness factors, eliminates CSCs via induction of DNA damage and apoptosis, opening future perspectives to avoid CSC driven therapy resistance and tumor relapse in PDAC patients.

Authors 23

1. Karolin Walter

   Universität Ulm · University Hospital Ulm

   Affiliation as printed

   Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

   Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany

2. Eva Rodríguez-Aznar

   Universität Ulm · University Hospital Ulm

   Affiliation as printed

   Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

   Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany

3. Mónica S. Ventura Ferreira Aachen Department of Hematology, Oncology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital of the RWTH Aachen, 52062 Aachen, Germany

   Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital of the RWTH Aachen, 506 Aachen, Germany

4. Pierre‐Olivier Frappart

   Universität Ulm · University Hospital Ulm

   Affiliation as printed

   Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

   Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany

5. Tabea Dittrich

   Universität Ulm · University Hospital Ulm

   Affiliation as printed

   Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

   Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany

6. Kanishka Tiwary

   Universität Ulm · University Hospital Ulm

   Affiliation as printed

   Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

   Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany

7. Sabine Meessen

   Universität Ulm

   Affiliation as printed

   Department of Urology, Ulm University, 89081 Ulm, Germany

8. Laura Lerma

   Koç University

   Affiliation as printed

   Department of Surgery, Koç University School of Medicine, 34450 Istanbul, Turkey

   Department of Surgery, Koç University School of Medicine, 350 Istanbul, Turkey

9. Nora Daiß

   Universität Ulm · University Hospital Ulm

   Affiliation as printed

   Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

   Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany

10. Lucas-Alexander Schulte

    Universität Ulm · University Hospital Ulm

    Affiliation as printed

    Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

    Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany

11. Frank Arnold

    Universität Ulm · University Hospital Ulm

    Affiliation as printed

    Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

    Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany

12. Valentyn Usachov

    Universität Ulm · University Hospital Ulm

    Affiliation as printed

    Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

    Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany

13. Ninel Azoitei

    Universität Ulm · University Hospital Ulm

    Affiliation as printed

    Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

    Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany

14. Mert Erkan

    Koç University · Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi

    Affiliation as printed

    Department of Surgery, Koç University School of Medicine, 34450 Istanbul, Turkey

    Research Center for Translational Medicine, Koç University, 34450 Istanbul, Turkey

    Department of Surgery, Koç University School of Medicine, 350 Istanbul, Turkey

    Research Center for Translational Medicine, Koç University, 3440 Istanbul, Turkey

15. André Lechel

    Universität Ulm · University Hospital Ulm

    Affiliation as printed

    Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

    Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany

16. Tim H. Brümmendorf Aachen Department of Hematology, Oncology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital of the RWTH Aachen, 52062 Aachen, Germany

    Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital of the RWTH Aachen, 506 Aachen, Germany

17. Thomas Theodor Werner Seufferlein

    Universität Ulm · University Hospital Ulm

    Affiliation as printed

    Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

    Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany

18. Alexander Kleger

    Universität Ulm · University Hospital Ulm

    Affiliation as printed

    Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

    Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany

19. E. Tabarés

    Universidad Autónoma de Madrid

    Affiliation as printed

    Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain

20. Çagatay Güneş

    Universität Ulm

    Affiliation as printed

    Department of Urology, Ulm University, 89081 Ulm, Germany

21. Fabian Beier Aachen Department of Hematology, Oncology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital of the RWTH Aachen, 52062 Aachen, Germany

    Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital of the RWTH Aachen, 506 Aachen, Germany

22. Bruno Sáinz

    Consejo Superior de Investigaciones Científicas · Instituto de Investigaciones Biomédicas Sols-Morreale · Instituto Ramón y Cajal de Investigación Sanitaria · Universidad Autónoma de Madrid

    Affiliation as printed

    Chronic Diseases and Cancer, Area 3 - Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28049 Madrid, Spain

    Department of Biochemistry, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain

    Department of Cancer Biology, Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM, 28049 Madrid, Spain

    Chronic Diseases and Cancer, Area 3 - Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 2804 Madrid, Spain

    Department of Cancer Biology, Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM), CSIC-UAM, 2049 Madrid, Spain

23. Patrick Christian Hermann corresponding

    Universität Ulm · University Hospital Ulm

    Affiliation as printed

    Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany

    Department of Internal Medicine I, University Medical Centre Ulm, 8908 Ulm, Germany