Publication:
Telomerase and pluripotency factors jointly regulate stemness in pancreatic cancer stem cells

dc.contributor.coauthorWalter, K.
dc.contributor.coauthorRodriguez-Aznar, E.
dc.contributor.coauthorVentura Ferreira, M. S.
dc.contributor.coauthorFrappart, P. -O.
dc.contributor.coauthorDittrich, T.
dc.contributor.coauthorTiwary, K.
dc.contributor.coauthorMeessen, S.
dc.contributor.coauthorLerma, L.
dc.contributor.coauthorDaiss, N.
dc.contributor.coauthorSchulte, L. -A.
dc.contributor.coauthorNajafova, Z.
dc.contributor.coauthorArnold, F.
dc.contributor.coauthorUsachov, V.
dc.contributor.coauthorAzoitei, N.
dc.contributor.coauthorLechel, A.
dc.contributor.coauthorBrümmendorf, T. H.
dc.contributor.coauthorSeufferlein, T.
dc.contributor.coauthorKleger, A.
dc.contributor.coauthorTabarés, E.
dc.contributor.coauthorGüneş, C.
dc.contributor.coauthorJohnsen, S. A.
dc.contributor.coauthorBeier, F.
dc.contributor.coauthorSainz, B. Jr.
dc.contributor.coauthorHermann, P. C.
dc.contributor.departmentKUTTAM (Koç University Research Center for Translational Medicine)
dc.contributor.departmentSchool of Medicine
dc.contributor.kuauthorErkan, Murat Mert
dc.contributor.schoolcollegeinstituteResearch Center
dc.contributor.schoolcollegeinstituteSCHOOL OF MEDICINE
dc.date.accessioned2024-11-09T11:46:55Z
dc.date.issued2021
dc.description.abstractSimple 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.
dc.description.fulltextYES
dc.description.indexedbyWOS
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.issue13
dc.description.openaccessYES
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuN/A
dc.description.sponsorshipMax Eder Fellowship of the German Cancer Aid
dc.description.sponsorshipGerman Cancer Aid Priority Program Translational Oncology
dc.description.sponsorshipCollaborative Research Centre Grant
dc.description.sponsorshipHector Foundation Cancer Research Grant
dc.description.sponsorshipRamon y Cajal Merit Award
dc.description.sponsorshipFundacion Asociacion Espanola Contra el Cancer (AECC) Coordinated Grant
dc.description.sponsorshipUlm University
dc.description.sponsorshipGerman Research Foundation
dc.description.sponsorshipMinisterio de Economia y Competitividad
dc.description.versionPublisher version
dc.description.volume13
dc.identifier.doi10.3390/cancers13133145
dc.identifier.eissn2072-6694
dc.identifier.embargoNO
dc.identifier.filenameinventorynoIR03014
dc.identifier.quartileQ2
dc.identifier.scopus2-s2.0-85108250030
dc.identifier.urihttps://hdl.handle.net/20.500.14288/546
dc.identifier.wos671238300001
dc.keywordsCancer stem cells
dc.keywordsPancreatic cancer
dc.keywordsSelf-renewal
dc.keywordsStemness
dc.keywordsTelomerase
dc.keywordsTelomere length
dc.language.isoeng
dc.publisherMultidisciplinary Digital Publishing Institute (MDPI)
dc.relation.grantno111746
dc.relation.grantno70112505
dc.relation.grantno316249678-SFB 1279
dc.relation.grantnoM65.1
dc.relation.grantnoRYC-2012-12104
dc.relation.grantnoGC16173694BARB
dc.relation.ispartofCancers
dc.relation.urihttp://cdm21054.contentdm.oclc.org/cdm/ref/collection/IR/id/9659
dc.subjectOncology
dc.titleTelomerase and pluripotency factors jointly regulate stemness in pancreatic cancer stem cells
dc.typeJournal Article
dspace.entity.typePublication
local.contributor.kuauthorErkan, Murat Mert
local.publication.orgunit1SCHOOL OF MEDICINE
local.publication.orgunit1Research Center
local.publication.orgunit2KUTTAM (Koç University Research Center for Translational Medicine)
local.publication.orgunit2School of Medicine
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