9 research outputs found
Vav proteins maintain epithelial traits in breast cancer cells using miR-200c-dependent and independent mechanisms
The bidirectional regulation of epithelial–mesenchymal transitions (EMT) is key in tumorigenesis. Rho GTPases regulate this process via canonical pathways that impinge on the stability of cell-to-cell contacts, cytoskeletal dynamics, and cell invasiveness. Here, we report that the Rho GTPase activators Vav2 and Vav3 utilize a new Rac1-dependent and miR-200c-dependent mechanism that maintains the epithelial state by limiting the abundance of the Zeb2 transcriptional repressor in breast cancer cells. In parallel, Vav proteins engage a mir-200c-independent expression prometastatic program that maintains epithelial cell traits only under 3D culture conditions. Consistent with this, the depletion of endogenous Vav proteins triggers mesenchymal features in epithelioid breast cancer cells. Conversely, the ectopic expression of an active version of Vav2 promotes mesenchymal-epithelial transitions using E-cadherin-dependent and independent mechanisms depending on the mesenchymal breast cancer cell line used. In silico analyses suggest that the negative Vav anti-EMT pathway is operative in luminal breast tumors. Gene signatures from the Vav-associated proepithelial and prometastatic programs have prognostic value in breast cancer patients.Fil: Lorenzo MartĂn, L. Francisco. Universidad de Salamanca; España. Consejo Superior de Investigaciones CientĂficas; España. Instituto de BiologĂa Molecular y Celular del Cáncer de Salamanca; EspañaFil: Citterio, Carmen. Consejo Superior de Investigaciones CientĂficas; España. Instituto de BiologĂa Molecular y Celular del Cáncer de Salamanca; EspañaFil: Menacho Márquez, Mauricio Ariel. Universidad de Salamanca; España. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Instituto de BiologĂa Molecular y Celular del Cáncer de Salamanca; EspañaFil: Conde, Javier. Consejo Superior de Investigaciones CientĂficas; España. Instituto de BiologĂa Molecular y Celular del Cáncer de Salamanca; EspañaFil: Larive, Romain M.. Consejo Superior de Investigaciones CientĂficas; España. Institut Des BiomolĂ©cules Max Mousseron; FranciaFil: RodrĂguez Fdez, Sonia. Consejo Superior de Investigaciones CientĂficas; EspañaFil: GarcĂa Escudero, RamĂłn. Consejo Superior de Investigaciones CientĂficas; España. Universidad de Salamanca; EspañaFil: Robles Valero, Javier. Universidad de Salamanca; España. Consejo Superior de Investigaciones CientĂficas; España. Centro de InvestigaciĂłn del Cáncer; España. Instituto de BiologĂa Molecular y Celular del Cáncer de Salamanca; EspañaFil: Cuadrado, Myriam. Universidad de Salamanca; España. Instituto de BiologĂa Molecular y Celular del Cáncer de Salamanca; España. Consejo Superior de Investigaciones CientĂficas; EspañaFil: Fernández Pisonero, Isabel. Universidad de Salamanca; España. Consejo Superior de Investigaciones CientĂficas; España. Instituto de BiologĂa Molecular y Celular del Cáncer de Salamanca; EspañaFil: Dosil, Mercedes. Universidad de Salamanca; España. Consejo Superior de Investigaciones CientĂficas; España. Instituto de BiologĂa Molecular y Celular del Cáncer de Salamanca; EspañaFil: Sevilla, MarĂa A.. Universidad de Salamanca; EspañaFil: Montero, MarĂa J.. Universidad de Salamanca; EspañaFil: Fernández Salguero, Pedro. Universidad de Extremadura; EspañaFil: Paramio, JesĂşs M.. Universidad de Salamanca; España. Consejo Superior de Investigaciones CientĂficas; España. Centro de Investigaciones EnergĂ©ticas, Medioambientales y TecnolĂłgicas; EspañaFil: Bustelo, XosĂ© R.. Universidad de Salamanca; España. Consejo Superior de Investigaciones CientĂficas; Españ
Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II
Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article, part II, we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. There are several studies demonstrating that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared to MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include “–omics” based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics and proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses