Pivotal role of AKT2 during dynamic phenotypic change of breast cancer stem cells
Gener, Petra (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Rafael, Diana (Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina)
Seras-Franzoso, Joaquin (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Pérez Martín, Anna (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Alamo Pindado, Luis (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Casas, Glòria (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Arango, Diego (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Fernández Caparrós, Yolanda (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Díaz Riascos, Zamira Vanessa. (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Abasolo, Ibane. (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Schwartz, Simó (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona

Data:	2019
Resum:	Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential.
Ajuts:	Instituto de Salud Carlos III PI17-02242 European Commission 800983
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cancer stem cells (CSC) ; Dynamic phenotype ; Epithelial-to-mesenchymal transition (EMT) ; AKT2 targeting
Publicat a:	Cancers, Vol. 11 Núm. 8 (august 2019) , p. 1058, ISSN 2072-6694

DOI: 10.3390/cancers11081058
PMID: 31357505

18 p, 3.3 MB

El registre apareix a les col·leccions:
Articles > Articles de recerca
Articles > Articles publicats