Abstract
Simple SummaryPancreatic 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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most frequent and the most lethal form of pancreatic cancer, and it is expected to be the second most frequent cause of cancerrelated death by 2030 [1]
Using well-established Cancer stem cells (CSCs) enrichment methods (i.e., CD133 or ALDEFLUOR fluorescence activated cell sorting (FACS), and sphere culture (Figure 1B)), we found increased expression of TERT and/or TERF1 in CD133+ cells (Figure 1C), ALDEFLUOR+ cells (Figure 1D) and in sphere cultures (Figure 1E) compared to the negative population or adherent cells, respectively
Using gel-based as well as PCR-based telomeric repeat amplification protocol (TRAP) assays, significantly higher telomerase activity was detected in the CSC fraction as compared to the respective control cells (Figure 1G–I)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most frequent and the most lethal form of pancreatic cancer, and it is expected to be the second most frequent cause of cancerrelated death by 2030 [1]. Despite growing knowledge about PDAC tumor biology, advances in treatment are still scarce, with FOLFIRINOX and gemcitabine + nabpaclitaxel currently representing the most promising combination chemotherapies [3,4]. The complexity and heterogeneity of pancreatic cancer remains only partially deciphered, and strategies for developing novel and more effective treatments are urgently needed. Cancer stem cells (CSCs) have been implicated in a wide variety of tumors. We and others have previously demonstrated their outstanding importance in pancreatic cancer perpetuation, metastasis, and therapy resistance [5,6]. As telomerase activity and telomere regulation have been proposed to play an essential role in tumor cell maintenance and are considered “hallmarks of cancer” by Hanahan and Weinberg, telomerase activity might present such a potential target
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
