Telomerase and Pluripotency Factors Jointly Regulate Stemness in Pancreatic Cancer Stem Cells
Karolin Walter, Eva Rodríguez-Aznar, Mónica S. Ventura Ferreira, Pierre‐Olivier Frappart, Tabea Dittrich, Kanishka Tiwary, Sabine Meessen, Laura Lerma, Nora Daiß, Lucas-Alexander Schulte, Zeynab Najafova, Frank Arnold, Valentyn Usachov, Ninel Azoitei, Mert Erkan, André Lechel, Tim H. Brümmendorf, Thomas Seufferlein, Alexander Kleger, E. Tabarés, Çagatay Güneş, Steven A. Johnsen, Fabian Beier, Bruno Sáinz, Patrick Hermann
Abstract
To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in 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 knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the "stemness" maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patients.