TY - JOUR
T1 - Telomerase and pluripotency factors jointly regulate stemness in pancreatic cancer stem cells
AU - Walter, Karolin
AU - Rodriguez-Aznar, Eva
AU - Ventura Ferreira, Monica S.
AU - Frappart, Pierre Olivier
AU - Dittrich, Tabea
AU - Tiwary, Kanishka
AU - Meessen, Sabine
AU - Lerma, Laura
AU - Daiss, Nora
AU - Schulte, Lucas Alexander
AU - Najafova, Zeynab
AU - Arnold, Frank
AU - Usachov, Valentyn
AU - Azoitei, Ninel
AU - Erkan, Mert
AU - Lechel, Andre
AU - Brümmendorf, Tim H.
AU - Seufferlein, Thomas
AU - Kleger, Alexander
AU - Tabarés, Enrique
AU - Günes, Cagatay
AU - Johnsen, Steven A.
AU - Beier, Fabian
AU - Sainz, Bruno
AU - Hermann, Patrick C.
N1 - Funding Information:
Funding: This research was funded by a Max Eder Fellowship of the German Cancer Aid (111746), a German Cancer Aid Priority Program ‘Translational Oncology’ 70112505, by a Collaborative Research Centre grant (316249678—SFB 1279) of the German Research Foundation, and by a Hector Foundation Cancer Research grant (M65.1) to P.C.H., B.S.J. is supported by a Rámon y Cajal Merit Award (RYC-2012-12104) from the Ministerio de Economía y Competitividad, Spain and a Coordinated grant (GC16173694BARB) from the Fundación Asociación Española Contra el Cáncer (AECC). K.W. is supported by a Baustein 3.2 by Ulm University.
Funding Information:
This research was funded by a Max Eder Fellowship of the German Cancer Aid (111746), a German Cancer Aid Priority Program ?Translational Oncology? 70112505, by a Collaborative Research Centre grant (316249678?SFB 1279) of the German Research Foundation, and by a Hector Foundation Cancer Research grant (M65.1) to P.C.H., B.S.J. is supported by a R?mon y Cajal Merit Award (RYC2012-12104) from the Ministerio de Econom?a y Competitividad, Spain and a Coordinated grant (GC16173694BARB) from the Fundaci?n Asociaci?n Espa?ola Contra el C?ncer (AECC). K.W. is supported by a Baustein 3.2 by Ulm University. We are indebted to Andrea Wi?mann and Kristina Diepold for excellent technical and experimental support. This report includes data that were generated as part of the doctoral thesis of K.W. at Ulm University. Technical illustrations in this manuscript were used from Servier Medical Art under a creative commons attribution 3.0 unported license.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - 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.
AB - 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.
KW - Cancer stem cells
KW - Pancreatic cancer
KW - Self-renewal
KW - Stemness
KW - Telomerase
KW - Telomere length
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UR - http://www.scopus.com/inward/citedby.url?scp=85108250030&partnerID=8YFLogxK
U2 - 10.3390/cancers13133145
DO - 10.3390/cancers13133145
M3 - Article
AN - SCOPUS:85108250030
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 13
M1 - 3145
ER -