000124441 001__ 124441
000124441 005__ 20241125101146.0
000124441 0247_ $$2doi$$a10.1016/j.biopha.2022.114162
000124441 0248_ $$2sideral$$a132845
000124441 037__ $$aART-2023-132845
000124441 041__ $$aeng
000124441 100__ $$aParejo-Alonso, Beatriz
000124441 245__ $$aPharmacological targeting of the receptor ALK inhibits tumorigenicity and overcomes chemoresistance in pancreatic ductal adenocarcinoma
000124441 260__ $$c2023
000124441 5060_ $$aAccess copy available to the general public$$fUnrestricted
000124441 5203_ $$aPancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease characterized by its metastatic potential and chemoresistance. These traits are partially attributable to the highly tumorigenic pancreatic cancer stem cells (PaCSCs). Interestingly, these cells show unique features in order to sustain their identity and functionality, some of them amenable for therapeutic intervention. Screening of phospho-receptor tyrosine kinases revealed that PaCSCs harbored increased activation of anaplastic lymphoma kinase (ALK). We subsequently demonstrated that oncogenic ALK signaling contributes to tumorigenicity in PDAC patient-derived xenografts (PDXs) by promoting stemness through ligand-dependent activation. Indeed, the ALK ligands midkine (MDK) or pleiotrophin (PTN) increased self-renewal, clonogenicity and CSC frequency in several in vitro local and metastatic PDX models. Conversely, treatment with the clinically-approved ALK inhibitors Crizotinib and Ensartinib decreased PaCSC content and functionality in vitro and in vivo, by inducing cell death. Strikingly, ALK inhibitors sensitized chemoresistant PaCSCs to Gemcitabine, as the most used chemotherapeutic agent for PDAC treatment. Consequently, ALK inhibition delayed tumor relapse after chemotherapy in vivo by effectively decreasing the content of PaCSCs. In summary, our results demonstrate that targeting the MDK/PTN-ALK axis with clinically-approved inhibitors impairs in vivo tumorigenicity and chemoresistance in PDAC suggesting a new treatment approach to improve the long-term survival of PDAC patients.
000124441 536__ $$9info:eu-repo/grantAgreement/ES/DGA/LMP29-21$$9info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI17-00082$$9info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI20-00921$$9info:eu-repo/grantAgreement/ES/ISCIII/FI21-00031$$9info:eu-repo/grantAgreement/ES/MS-ISCIII-FSE/CP16-00121
000124441 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
000124441 590__ $$a6.9$$b2023
000124441 592__ $$a1.493$$b2023
000124441 591__ $$aPHARMACOLOGY & PHARMACY$$b15 / 354 = 0.042$$c2023$$dQ1$$eT1
000124441 593__ $$aPharmacology$$c2023$$dQ1
000124441 591__ $$aMEDICINE, RESEARCH & EXPERIMENTAL$$b22 / 189 = 0.116$$c2023$$dQ1$$eT1
000124441 593__ $$aMedicine (miscellaneous)$$c2023$$dQ1
000124441 594__ $$a11.9$$b2023
000124441 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000124441 700__ $$aRoyo-García, Alba
000124441 700__ $$aEspiau-Romera, Pilar
000124441 700__ $$aCourtois, Sarah
000124441 700__ $$aCuriel-García, Álvaro
000124441 700__ $$aZagorac, Sladjana
000124441 700__ $$aVillaoslada, Isabel
000124441 700__ $$aOlive, Kenneth P.
000124441 700__ $$aHeeschen, Christopher
000124441 700__ $$aSancho, Patricia
000124441 773__ $$g158 (2023), 114162 [14 pp.]$$pBiomed. pharmacother.$$tBIOMEDICINE & PHARMACOTHERAPY$$x0753-3322
000124441 8564_ $$s7006658$$uhttps://zaguan.unizar.es/record/124441/files/texto_completo.pdf$$yVersión publicada
000124441 8564_ $$s2561827$$uhttps://zaguan.unizar.es/record/124441/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000124441 909CO $$ooai:zaguan.unizar.es:124441$$particulos$$pdriver
000124441 951__ $$a2024-11-22-12:04:31
000124441 980__ $$aARTICLE