1. Telomerase and pluripotency factors jointly regulate stemness in pancreatic cancer stem cells
- Author
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Erkan, Murat Mert (ORCID 0000-0002-2753-0234 & YÖK ID 214689), Walter, K.; Rodriguez-Aznar, E.; Ventura Ferreira, M. S.; Frappart, P. -O.; Dittrich, T.; Tiwary, K.; Meessen, S.; Lerma, L.; Daiss, N.; Schulte, L. -A.; Najafova, Z.; Arnold, F.; Usachov, V.; Azoitei, N.; Lechel, A.; Brümmendorf, T. H.; Seufferlein, T.; Kleger, A.; Tabarés, E.; Güneş, C.; Johnsen, S. A.; Beier, F.; Sainz, B. Jr.; Hermann, P. C., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Erkan, Murat Mert (ORCID 0000-0002-2753-0234 & YÖK ID 214689), Walter, K.; Rodriguez-Aznar, E.; Ventura Ferreira, M. S.; Frappart, P. -O.; Dittrich, T.; Tiwary, K.; Meessen, S.; Lerma, L.; Daiss, N.; Schulte, L. -A.; Najafova, Z.; Arnold, F.; Usachov, V.; Azoitei, N.; Lechel, A.; Brümmendorf, T. H.; Seufferlein, T.; Kleger, A.; Tabarés, E.; Güneş, C.; Johnsen, S. A.; Beier, F.; Sainz, B. Jr.; Hermann, P. C., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine
- Abstract
Simple summary: pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal cancer with very limited therapeutic options. Cancer stem cells (CSCs) are essential for propagation of PDAC, but also for its metastatic activity and chemoresistance. To date, it is still unclear how cancer stem cells (CSCs) regulate their 'stemness' and self-renewal properties, and to what extent they share common features with normal stem cells. Telomerase regulation is a key factor in stem cell maintenance. Here, we investigate how telomerase regulation affects CSC biology in PDAC, and delineate the mechanisms by which telomerase activity and CSC properties are linked. 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., Max Eder Fellowship of the German Cancer Aid; German Cancer Aid Priority Program Translational Oncology; Collaborative Research Centre Grant; Hector Foundation Cancer Research Grant; Ramon y Cajal Merit Award; Fundacion Asociacion Espanola Contra el Cancer (AECC) Coordinated Grant; Ulm University; German Research Foundation; Ministerio de Economia y Competitividad
- Published
- 2021