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1. RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade

Author

Nokin, Marie-Julie, Mira, Alessia, Patrucco, Enrico, Ricciuti, Biagio, Cousin, Sophie, Soubeyran, Isabelle, San José, Sonia, Peirone, Serena, Caizzi, Livia, Vietti Michelina, Sandra, Bourdon, Aurelien, Wang, Xinan, Alvarez-Villanueva, Daniel, Martínez-Iniesta, María, Vidal, August, Rodrigues, Telmo, García-Macías, Carmen, Awad, Mark M., Nadal, Ernest, Villanueva, Alberto, Italiano, Antoine, Cereda, Matteo, Santamaría, David, and Ambrogio, Chiara

Published
2024
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3. Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Author

Gómez-Vecino, Aurora, Corchado-Cobos, Roberto, Blanco-Gómez, Adrián, García-Sancha, Natalia, Castillo-Lluva, Sonia, Martín-García, Ana, Mendiburu-Eliçabe, Marina, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, Carmen, Galindo-Villardón, Purificación, Vera-Pedrosa, María, Jalife, José, Macías de Plasencia, Guillermo, Castellanos-Martín, Andrés, Sáez-Freire, María, Fraile-Martín, Susana, Rodrigues-Teixeira, Telmo, García-Macías, Carmen, Galvis-Jiménez, Julie, García-Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, María, García-Criado, Francisco, García-Hernández, Juan, Hernández-García, María, Cruz-Hernández, Juan, Rodríguez-Sánchez, César, García-Sancho, Alejandro, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio, García-Sáenz, José, Patiño-García, Ana, Martín, Miguel, Alonso-Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Chang, Hang, Holgado-Madruga, Marina, González-Neira, Anna, Sánchez, Pedro, Pérez Losada, Jesús, and Mao, Jian-Hua

Subjects
anthracyclines, cardiotoxicity, complex genetic disease, intermediate molecular phenotypes, quantitative trait loci, Female, Animals, Mice, Cardiotoxicity, Anthracyclines, Genetic Markers, Antibiotics, Antineoplastic, Neoplasms, Phenotype
Abstract

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Published
2023

5. Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk

Author

Gómez Vecino, Aurora, Corchado Cobos, Roberto, Blanco Gómez, Adrián, García Sancha, Natalia, Martín García, Ana, Mendiburu-Eliçabe Garganta, Marina, Prieto, Carlos, Ruiz Pinto, Sara, Pita, Guillermo, Velasco Ruiz, Alejandro, Patino Alonso, Carmen, Galindo Villardón, Purificación, Linarejos Vera Pedrosa, María, Jalife, José, Mao, Jian-Hua, Macías de Plasencia, Guillermo, Castellanos Martín, Andrés, Sáez Freire, María del Mar, Fraile Martín, Susana, Rodrigues Teixeira, Telmo, García Macías, Carmen, Galvis Jiménez, Julie Milena, Castillo Lluva, Sonia, García Sánchez, Asunción, Isidoro García, María, Fuentes, Manuel, García-Cenador, María Begoña, García-Criado, Francisco Javier, García-Hernández, Juan Luis, Hernández-García, María Ángeles, Cruz-Hernández, Juan Jesús, Rodríguez-Sánchez, César Augusto, Martín García-Sancho, Alejandro, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J., García-Sáenz, José Ángel, Patiño-García, Ana, Martín, Miguel, Alonso-Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Hang, Chang, Holgado-Madruga, Marina, González-Neira, Anna, Sánchez, Pedro L., Pérez Losada, Jesús, Gómez Vecino, Aurora, Corchado Cobos, Roberto, Blanco Gómez, Adrián, García Sancha, Natalia, Martín García, Ana, Mendiburu-Eliçabe Garganta, Marina, Prieto, Carlos, Ruiz Pinto, Sara, Pita, Guillermo, Velasco Ruiz, Alejandro, Patino Alonso, Carmen, Galindo Villardón, Purificación, Linarejos Vera Pedrosa, María, Jalife, José, Mao, Jian-Hua, Macías de Plasencia, Guillermo, Castellanos Martín, Andrés, Sáez Freire, María del Mar, Fraile Martín, Susana, Rodrigues Teixeira, Telmo, García Macías, Carmen, Galvis Jiménez, Julie Milena, Castillo Lluva, Sonia, García Sánchez, Asunción, Isidoro García, María, Fuentes, Manuel, García-Cenador, María Begoña, García-Criado, Francisco Javier, García-Hernández, Juan Luis, Hernández-García, María Ángeles, Cruz-Hernández, Juan Jesús, Rodríguez-Sánchez, César Augusto, Martín García-Sancho, Alejandro, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J., García-Sáenz, José Ángel, Patiño-García, Ana, Martín, Miguel, Alonso-Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Hang, Chang, Holgado-Madruga, Marina, González-Neira, Anna, Sánchez, Pedro L., and Pérez Losada, Jesús

Abstract

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management., Ministerio de Ciencia, Innovación y Universidades (España), European Comission, Junta de Castilla y León, Instituto de Salud Carlos III, Ministerio de Economía, Comercio y Empresa (España), Federación Española de Enfermedades Raras, Departamento de Defensa (Estados Unidos), National Institutes of Health (Estados Unidos), Universidad de California (Estados Unidos), Instituto Nacional del Cáncer (Estados Unidos), Fundación "la Caixa", Agencia Estatal de Investigación, Depto. de Estadística e Investigación Operativa, Fac. de Farmacia, TRUE, pub

Published
2023

6. Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk

Author

Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Junta de Castilla y León, Instituto de Salud Carlos III, Department of Defense (US), National Institutes of Health (US), National Cancer Institute (US), Lawrence Berkeley National Laboratory, Fundación la Caixa, Centro Nacional de Investigaciones Cardiovasculares (España), Gómez-Vecino, Aurora, Corchado Cobos, Roberto, Blanco-Gómez, Adrián, García-Sancha, Natalia, Castillo-Lluva, Sonia, Martin-Garcia, Ana, Mendiburu-Eliçabe, Marina, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Linarejos Vera-Pedrosa, María, Jalife, José, Mao, Jian-Hua, Macías de Plasencia, Guillermo, Castellanos-Martín, Andrés, Sáez-Freire, María Del Mar, Fraile, Susana, Rodrigues Teixeira, Telmo, García-Macías, Carmen, Galvis-Jiménez, Julie Milena, García Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, Begoña, García-Criado, Francisco Javier, García, Juan L., Hernández-García, María Ángeles, Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, García-Sancho, Alejandro Martín, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J, García-Sáenz, José Ángel, Patiño-García, Ana, Martín, Miguel, Alonso Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Chang, Hang, Holgado-Madruga, M., González-Neira, Anna, Sánchez, Pedro L, Pérez-Losada, J., Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Junta de Castilla y León, Instituto de Salud Carlos III, Department of Defense (US), National Institutes of Health (US), National Cancer Institute (US), Lawrence Berkeley National Laboratory, Fundación la Caixa, Centro Nacional de Investigaciones Cardiovasculares (España), Gómez-Vecino, Aurora, Corchado Cobos, Roberto, Blanco-Gómez, Adrián, García-Sancha, Natalia, Castillo-Lluva, Sonia, Martin-Garcia, Ana, Mendiburu-Eliçabe, Marina, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Linarejos Vera-Pedrosa, María, Jalife, José, Mao, Jian-Hua, Macías de Plasencia, Guillermo, Castellanos-Martín, Andrés, Sáez-Freire, María Del Mar, Fraile, Susana, Rodrigues Teixeira, Telmo, García-Macías, Carmen, Galvis-Jiménez, Julie Milena, García Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, Begoña, García-Criado, Francisco Javier, García, Juan L., Hernández-García, María Ángeles, Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, García-Sancho, Alejandro Martín, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J, García-Sáenz, José Ángel, Patiño-García, Ana, Martín, Miguel, Alonso Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Chang, Hang, Holgado-Madruga, M., González-Neira, Anna, Sánchez, Pedro L, and Pérez-Losada, J.

Abstract

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Published
2023

7. Intermediate molecular phenotypes to identify genetic markers of anthracycline-induced cardiotoxicity risk

Author

Gómez-Vecino, Aurora, primary, Corchado-Cobos, Roberto, additional, Blanco-Gómez, Adrián, additional, García-Sancha, Natalia, additional, Castillo-Lluva, Sonia, additional, Martín-García, Ana, additional, Mendiburu-Eliçabe, Marina, additional, Prieto, Carlos, additional, Ruiz-Pinto, Sara, additional, Pita, Guillermo, additional, Velasco-Ruiz, Alejandro, additional, Patino-Alonso, Carmen, additional, Galindo-Villardón, Purificación, additional, Vera-Pedrosa, María Linarejos, additional, Jalife, José, additional, Mao, Jian-Hua, additional, de Plasencia, Guillermo Macías, additional, Castellanos-Martín, Andrés, additional, del Mar Sáez Freire, María, additional, Fraile-Martín, Susana, additional, Rodrigues-Teixeira, Telmo, additional, García-Macías, Carmen, additional, Galvis-Jiménez, Julie Milena, additional, García-Sánchez, Asunción, additional, Isidoro-García, María, additional, Fuentes, Manuel, additional, García-Cenador, María Begoña, additional, García-Criado, Francisco Javier, additional, García, Juan Luis, additional, Hernández-García, María Ángeles, additional, Cruz Hernández, Juan Jesús, additional, Rodríguez-Sánchez, César Augusto, additional, Martín-Ruiz, Alejandro, additional, Pérez-López, Estefanía, additional, Pérez-Martínez, Antonio, additional, Gutiérrez-Larraya, Federico, additional, Cartón, Antonio J., additional, García-Sáenz, José Ángel, additional, Patiño-García, Ana, additional, Martín, Miguel, additional, Gordoa, Teresa Alonso, additional, Vulsteke, Christof, additional, Croes, Lieselot, additional, Hatse, Sigrid, additional, Van Brussel, Thomas, additional, Lambrechts, Diether, additional, Wildiers, Hans, additional, Hang, Chang, additional, Holgado-Madruga, Marina, additional, González-Neira, Anna, additional, Sánchez, Pedro L, additional, and Pérez Losada, Jesús, additional

Published
2023
Full Text
View/download PDF

8. Additional file 9 of Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia [Dataset]

Author

Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, Alarcón, Balbino, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, and Alarcón, Balbino

Published
2022

9. Additional file 5 of Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia [Dataset]

Author

Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, Alarcón, Balbino, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, and Alarcón, Balbino

Abstract

Additional file 5: Figure S5. a, Principal component analysis of CD19 + CD21-CD23+ follicular B cells from Rosa26-RRAS2xmb1-Cre mice, CD19 + CD21-CD23+ follicular B cells from WT C57BL/6 J mice and of leukemic CD19 + CD5+, GFPlow and GFPhigh cells from Rosa26-RRAS2xmb1-Cre mice. b, Ingenuity Pathway Analysis (IPA) of differentially expressed genes associated with molecular mechanisms of cancer in leukemic versus normal follicular B cells. Pink-filled symbols: upregulated genes. Green-filled: downregulated genes. Double circle: protein complex; horizontal ellipse: transcription regulator; vertical ellipse: transmembrane receptor, diamond: enzyme; trapezium: transporter; triangle: phosphatase; inverted triangle: kinase; vertical rectangle: G protein-coupled receptor; circle: other. Black arrows: direct interactions; grey/white arrows: indirect interactions. Relationship labels: A: activation; B: binding; C: causation; CO: correlation; E: expression; EC: enzyme catalysis; I: inhibition; L: molecular cleavage; LO: localization; M: biochemical modification; miT: microRNA Targeting; P: phosphorylation/dephosphorylation; PD: protein-DNA binding; PP: protein-protein binding; PR: protein-RNA binding, RB: regulation of binding; RE: reaction; T: transcription; TR: translocation; UB: ubiquitination.

Published
2022

10. Additional file 7 of Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia [Dataset]

Author

Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, Alarcón, Balbino, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, and Alarcón, Balbino

Abstract

Additional file 7: Figure S7. Ingenuity Pathway Analysis (IPA) of differentially expressed genes associated with mTOR signaling, immunological development, and G1-S checkpoint regulation in leukemic versus normal follicular B cells. Pink-filled symbols: upregulated genes. Green-filled: downregulated genes. Double circle: protein complex; horizontal ellipse: transcription regulator; vertical ellipse: transmembrane receptor, diamond: enzyme; trapezium: transporter; triangle: phosphatase; inverted triangle: kinase; vertical rectangle: G protein-coupled receptor; circle: other. Black arrows: direct interactions; grey/white arrows: indirect interactions. Relationship labels: A: activation; B: binding; C: causation; CO: correlation; E: expression; EC: enzyme catalysis; I: inhibition; L: molecular cleavage; LO: localization; M: biochemical modification; miT: microRNA Targeting; P: phosphorylation/dephosphorylation; PD: protein-DNA binding; PP: protein-protein binding; PR: protein-RNA binding, RB: regulation of binding; RE: reaction; T: transcription; TR: translocation; UB: ubiquitination.

Published
2022

11. Additional file 3 of Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia [Dataset]

Author

Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, Alarcón, Balbino, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, and Alarcón, Balbino

Abstract

Additional file 3: Figure S3. a, Representative two-color contour plots of B cell populations in a peritoneal wash and the spleen of 12 wk-old mice according to the expression of the CD11b and CD5 markers in the CD19+ population. The blue square indicates CD11b + CD5- B1b cells in the peritoneum. Red square, the presence of CD11b + CD5+ B1a cells in control mice and leukemic cells. Quantification of CD11b + CD5+ cells is shown to the right in box and whiskers plots showing all points and median value. **p < 0.01; *** p < 0.001, two-tailed unpaired t-test with Welch’s correction. b, Representative two-color contour plots of IgM and GFP expression within the CD11b + CD5+ populations shown in a. Quantification of IgMbright cells within the CD11b + CD5+ B cell population is shown to the right in box and whiskers plots showing all points and median value. **** p < 0.0001, two-tailed unpaired t-test with Welch’s correction.

Published
2022

12. Additional file 6 of Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia [Dataset]

Author

Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, Alarcón, Balbino, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, and Alarcón, Balbino

Abstract

Additional file 6: Figure S6. a, Mutations found in human cancer involving the RRAS2 gene. Data obtained from cBioPortal (97,250 patients/100669 samples). Refseq: NM_012250. Ensembl: ENST00000256196. CCDS: CCDS7814. Uniprot: RRAS2_HUMAN. Missense mutations (green dots): 36. Truncating mutations (black dots): 6. Splice mutations (orange dots): 5. b, Quantification by RT-qPCR or total mouse (Rras2) and human (RRAS2) mRNA expression in purified splenic CD19+ B cells from Rras2(Q72L)fl/fl xmb1-Cre (Q72L) mice compared to purified B CD19+ B cells from control WT C57BL/6 mice and to CD19 + CD5+ leukemic B cells from Rosa26-RRAS2fl/flxmb1-Cre mice. Results show data obtained in triplicate normalized to the C57BL/6 control for n = 3 mice per group. All mice were 14 month-old. Data show means ± SEM for three mice per group. *p < 0.05; ns. Not significant (one-way ANOVA test). c, Left, quantification by flow cytometry of total B-cell number in spleens of 14 month-old control and Rras2(Q72L)fl/fl xmb1-Cre mice. Right, two-parameter flow cytometry plot showing frequency of IgM + CD5+ cells within CD19+ splenic B cells of control and Rras2(Q72L)fl/fl xmb1-Cre mice. d, Left, concentration of B-cells per microliter in blood of control and Rras2(Q72L)fl/fl xmb1-Cre mice. Right, two-parameter flow cytometry plot showing frequency of CD19 + CD5+ cells within blood B cells of control and Rras2(Q72L)fl/fl xmb1-Cre mice. e, Frequency of marginal zone (MZ) phenotype (CD21high, CD23low), and follicular (CD21low, CD23high) B cells within CD19+ splenic B cells of control and Rras2(Q72L)fl/fl xmb1-Cre mice. f, Phosflow cytometry analysis of different elements from PI3K-Akt-mTOR, Raf-Erk and proximal BCR signaling pathways. Wild-type CD19+ follicular B cells, CD19 + CD5+ leukemic cells from spleens of Rosa26-RRAS2fl/flxmb1-Cre mice and CD19+ non-leukemic B cells from Rras2(Q72L)fl/fl xmb1-Cre are shown. In grey, background fluorescence of the secondary antibodies. All mice were 23 wk-old. Dat

Published
2022

13. Additional file 4 of Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia [Dataset]

Author

Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, Alarcón, Balbino, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, and Alarcón, Balbino

Abstract

Additional file 4: Figure S4. a, Representative two-color contour plots of lymphoid populations in liver and spleen from 2 wk-old mice according to the expression of CD19 and CD5 and within the CD19 + CD5+ population according to the expression of CD21, B220, CD24, CD23 and CD38 markers. b, Column plots show the quantification of the percentage of CD19 + CD5+ B cells in liver and spleen bearing the markers shown in a. n = 4 mice per group. ** p < 0.01 ****p < 0.0001, ns, not significant (one-way ANOVA test).

Published
2022

14. Additional file 11 of Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia [Dataset]

Author

Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, Alarcón, Balbino, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, and Alarcón, Balbino

Published
2022

15. Additional file 8 of Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia [Dataset]

Author

Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, Alarcón, Balbino, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), European Research Council, Instituto de Salud Carlos III, Junta de Castilla y León, Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, and Alarcón, Balbino

Published
2022

16. Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia

Author

Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Comisión Interministerial de Ciencia y Tecnología, CICYT (España), Fundación Ramón Areces, European Research Council, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Cáncer (España), Junta de Castilla y León, Ministerio de Economía y Competitividad (España), Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, Alarcón, Balbino, Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Comisión Interministerial de Ciencia y Tecnología, CICYT (España), Fundación Ramón Areces, European Research Council, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Cáncer (España), Junta de Castilla y León, Ministerio de Economía y Competitividad (España), Hortal, Alejandro, Oeste, Clara L., Cifuentes, Claudia, Alcoceba, Miguel, Fernández-Pisonero, Isabel, Clavaín, Laura, Tercero, Rut, Mendoza, Pilar, Domínguez, Verónica, García-Flores, Marta, Pintado, Belén, Abia, David, García-Macías, Carmen, Navarro-Bailón, Almudena, Bustelo, Xosé R., González, Marcos, and Alarcón, Balbino

Abstract

[Background]: Chronic lymphocytic leukemia (CLL) is the most frequent, and still incurable, form of leukemia in the Western World. It is widely accepted that cancer results from an evolutionary process shaped by the acquisition of driver mutations which confer selective growth advantage to cells that harbor them. Clear examples are missense mutations in classic RAS genes (KRAS, HRAS and NRAS) that underlie the development of approximately 13% of human cancers. Although autonomous B cell antigen receptor (BCR) signaling is involved and mutations in many tumor suppressor genes and oncogenes have been identified, an oncogenic driver gene has not still been identified for CLL. [Methods]: Conditional knock-in mice were generated to overexpress wild type RRAS2 and prove its driver role. RT-qPCR analysis of a human CLL sample cohort was carried out to measure RRAS2 transcriptional expression. Sanger DNA sequencing was used to identify a SNP in the 3’UTR region of RRAS2 in human CLL samples. RNAseq of murine CLL was carried out to identify activated pathways, molecular mechanisms and to pinpoint somatic mutations accompanying RRAS2 overexpression. Flow cytometry was used for phenotypic characterization and shRNA techniques to knockdown RRAS2 expression in human CLL. [Results]: RRAS2 mRNA is found overexpressed in its wild type form in 82% of the human CLL samples analyzed (n = 178, mean and median = 5-fold) as well as in the explored metadata. A single nucleotide polymorphism (rs8570) in the 3’UTR of the RRAS2 mRNA has been identified in CLL patients, linking higher expression of RRAS2 with more aggressive disease. Deliberate overexpression of wild type RRAS2 in mice, but not an oncogenic Q72L mutation in the coding sequence, provokes the development of CLL. Overexpression of wild type RRAS2 in mice is accompanied by a strong convergent selection of somatic mutations in genes that have been identified in human CLL. R-RAS2 protein is physically bound to the BCR and mediates

Published
2022

17. A hotspot mutation targeting the R-RAS2 GTPase acts as a potent oncogenic driver in a wide spectrum of tumors

Author

Asociación Española Contra el Cáncer, Junta de Castilla y León, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, La Caixa, Instituto de Salud Carlos III, Ministerio de Educación, Cultura y Deporte (España), Fernández-Pisonero, Isabel, Clavaín, Laura, Robles-Valero, Javier, Lorenzo-Martín, L. Francisco, Caloto, Rubén, Nieto, Blanca, García-Macías, Carmen, Oeste, Clara L., Sánchez-Martín, M., Abad, Antonio, Hortal, Alejandro, Caballero, Dolores, González, Marcos, Dosil, Mercedes, Bustelo, Xosé R., Asociación Española Contra el Cáncer, Junta de Castilla y León, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, La Caixa, Instituto de Salud Carlos III, Ministerio de Educación, Cultura y Deporte (España), Fernández-Pisonero, Isabel, Clavaín, Laura, Robles-Valero, Javier, Lorenzo-Martín, L. Francisco, Caloto, Rubén, Nieto, Blanca, García-Macías, Carmen, Oeste, Clara L., Sánchez-Martín, M., Abad, Antonio, Hortal, Alejandro, Caballero, Dolores, González, Marcos, Dosil, Mercedes, and Bustelo, Xosé R.

Abstract

A missense change in RRAS2 (Gln to Leu), analogous to the Gln-to-Leu mutation of RAS oncoproteins, has been identified as a long-tail hotspot mutation in cancer and Noonan syndrome. However, the relevance of this mutation for in vivo tumorigenesis remains understudied. Here we show, using an inducible knockin mouse model, that R-Ras2 triggers rapid development of a wide spectrum of tumors when somatically expressed in adult tissues. These tumors show limited overlap with those originated by classical Ras oncogenes. R-Ras2-driven tumors can be classified into different subtypes according to therapeutic susceptibility. Importantly, the most relevant R-Ras2-driven tumors are dependent on mTORC1 but independent of phosphatidylinositol 3-kinase-, MEK-, and Ral guanosine diphosphate (GDP) dissociation stimulator. This pharmacological vulnerability is due to the extensive rewiring by R-Ras2 of pathways that orthogonally stimulate mTORC1 signaling. These findings demonstrate that RRAS2 is a bona fide oncogenic driver and unveil therapeutic strategies for patients with cancer and Noonan syndrome bearing RRAS2 mutations.

Published
2022

18. A hotspot mutation targeting the R-RAS2 GTPase acts as a potent oncogenic driver in a wide spectrum of tumors

Author

Fernández-Pisonero, Isabel, primary, Clavaín, Laura, additional, Robles-Valero, Javier, additional, Lorenzo-Martín, L. Francisco, additional, Caloto, Rubén, additional, Nieto, Blanca, additional, García-Macías, Carmen, additional, Oeste, Clara L., additional, Sánchez-Martín, Manuel, additional, Abad, Antonio, additional, Hortal, Alejandro, additional, Caballero, Dolores, additional, González, Marcos, additional, Dosil, Mercedes, additional, Alarcón, Balbino, additional, and Bustelo, Xosé R., additional

Published
2022
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19. Granuloma formation in a cyba-deficient model of chronic granulomatous disease is associated with myeloid hyperplasia and the exhaustion of B-cell lineage

Author

Junta de Castilla y León, European Commission, Prieto-Bermejo, Rodrigo, Romo-González, Marta, Pérez-Fernández, Alejandro, García-Macías, Carmen, Sánchez-Bernal, Carmen, García-Tuñón, Ignacio, Sánchez-Yagüe, Jesús, Sánchez-Martín, M., Hernández-Hernández, Ángel, Junta de Castilla y León, European Commission, Prieto-Bermejo, Rodrigo, Romo-González, Marta, Pérez-Fernández, Alejandro, García-Macías, Carmen, Sánchez-Bernal, Carmen, García-Tuñón, Ignacio, Sánchez-Yagüe, Jesús, Sánchez-Martín, M., and Hernández-Hernández, Ángel

Abstract

Haematopoiesis is a paradigm of cell differentiation because of the wide variety and overwhelming number of mature blood cells produced daily. Under stress conditions, the organism must adapt to a boosted demand for blood cells. Chronic granulomatous disease (CGD) is a genetic disease caused by inactivating mutations that affect the phagocyte oxidase. Besides a defective innate immune system, CGD patients suffer from recurrent hyper-inflammation episodes, circumstances upon which they must face emergency haematopoiesis. The targeting of Cybb and Ncf1 genes have produced CGD animal models that are a useful surrogate when studying the pathophysiology and treatment of this disease. Here, we show that Cyba−/− mice spontaneously develop granuloma and, therefore, constitute a CGD animal model to complement the existing Cybb−/− and Ncf1−/− models. More importantly, we have analysed haematopoiesis in granuloma-bearing Cyba−/− mice. These animals showed a significant loss of weight, developed remarkable splenomegaly, bone marrow myeloid hyperplasia, and signs of anaemia. Haematological analyses showed a sharped decrease of B-cells and a striking development of myeloid cells in all compartments. Collectively, our results show that granuloma inflammatory lesions dramatically change haematopoiesis homeostasis. Consequently, we suggest that besides their defective innate immunity, the alteration of haematopoiesis homeostasis upon granuloma may contribute to the dismal outcome of CGD.

Published
2021

20. Datasets related to a study aimed to identify genetic markers of CDA by subphenotypes associated with cardiotoxicity

Author

European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Castilla y León, Fundación la Caixa, Centro Nacional de Investigaciones Cardiovasculares (España), Pérez-Losada, J. [0000-0003-2400-624X], Macías de Plasencia, Guillermo, Fraile, Susana, Rodrigues Teixeira, Telmo, Hernández-García, María Ángeles, Holgado-Madruga, M., González-Neira, Ana, Sánchez, Pedro L., Pérez-Losada, J., Gómez-Vecino, Aurora, Corchado Cobos, Roberto, Blanco-Gómez, Adrián, Castillo, Sonia, García-Sancha, Natalia, Martin-Garcia, Ana, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Linarejos Vera-Pedrosa, María, Jalife, José, Castellanos-Martín, Andrés, Sáez-Freire, María del Mar, Mendiburu-Eliçabe, Marina, García-Macías, Carmen, Galvis-Jiménez, Julie Milena, García-Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, Begoña, García-Criado, Francisco Javier, García, Juan L., Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, Martín-Ruiz, Alejandro, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J., García-Saenz, José Ángel, Patiño-García, Ana, Martin, Miguel, Alonso Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Martín, Miguel A., European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Castilla y León, Fundación la Caixa, Centro Nacional de Investigaciones Cardiovasculares (España), Pérez-Losada, J. [0000-0003-2400-624X], Macías de Plasencia, Guillermo, Fraile, Susana, Rodrigues Teixeira, Telmo, Hernández-García, María Ángeles, Holgado-Madruga, M., González-Neira, Ana, Sánchez, Pedro L., Pérez-Losada, J., Gómez-Vecino, Aurora, Corchado Cobos, Roberto, Blanco-Gómez, Adrián, Castillo, Sonia, García-Sancha, Natalia, Martin-Garcia, Ana, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Linarejos Vera-Pedrosa, María, Jalife, José, Castellanos-Martín, Andrés, Sáez-Freire, María del Mar, Mendiburu-Eliçabe, Marina, García-Macías, Carmen, Galvis-Jiménez, Julie Milena, García-Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, Begoña, García-Criado, Francisco Javier, García, Juan L., Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, Martín-Ruiz, Alejandro, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J., García-Saenz, José Ángel, Patiño-García, Ana, Martin, Miguel, Alonso Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, and Martín, Miguel A.

Abstract

Here we present a series of supplemental datasets that complement our study entitled "A Systems Genetics approach to identify genetic markers of cardiotoxicity due to anthracyclines in cancer patients." The datasets presented here were used to generate the main and supplementary figures and tables of the indicated study. The study consists of the identification of genetic markers of cardiotoxicity due to anthracyclines (CDA). CDA is a complex genesis disease or complex trait, and because of this, there is a component of missing heritability. Therefore, it is not possible to identify genetic markers associated with CDA risk. Here, we propose that molecular subphenotypes associated with the CDA may be a strategy for identifying some of this missing heritability and risk markers associated with it. A similar strategy could be applied to identify markers of other diseases of complex genesis. This study is done using a genetically heterogeneous cohort of mice that developed breast cancer and was treated with doxorubicin or a combined treatment of doxorubicin and docetaxel. The mouse cohort was generated by backcrossing, so each mouse is genetically unique. Post-chemotherapy heart damage was assessed by quantifying fibrosis's cardiac area and the thickness of myocardial fibers. The genetic regions associated with CDA were assessed by massive genotyping and genetic linkage analysis. Several molecular subphenotypes were quantified in the myocardium, and their association with the CDA was evaluated. Subsequently, we identified which of them were most statistically associated with CDA in multivariate models. Moreover, which complex trait loci (QTLs) associated with molecular subphenotypes best explained CDA. This strategy served to identify in the cohort of mice genes whose allelic forms could be candidates for the risk of CDA. Allelic variants of these genes were evaluated in four cohorts of cancer patients treated with anthracyclines and whose CDA was evaluated by echocardi

Published
2021

22. VAV2 signaling promotes regenerative proliferation in both cutaneous and head and neck squamous cell carcinoma

Author

Worldwide Cancer Research, Junta de Castilla y León, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Ramón Areces, Asociación Española Contra el Cáncer, European Research Council, Ministerio de Educación, Cultura y Deporte (España), European Commission, Lorenzo-Martín, L. Francisco, Fernández-Parejo, Natalia, Menacho-Márquez, Mauricio, Rodríguez-Fdez, Sonia, Robles-Valero, Javier, Zumalave, Sonia, Salvatore, Fabbiano, Pascual, Gloria, García-Pedrero, Juana María, Abad, Antonio, García-Macías, Carmen, González, Nazareno, Lorenzano Menna, Pablo, Pavón, Miguel A., González-Sarmiento, Rogelio, Segrelles, Carmen, Paramio, Jesús M., Tubío, José M. C., Rodrigo, Juan Pablo, Benitah, Salvador A., Cuadrado, Myriam, Bustelo, Xosé R., Worldwide Cancer Research, Junta de Castilla y León, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Ramón Areces, Asociación Española Contra el Cáncer, European Research Council, Ministerio de Educación, Cultura y Deporte (España), European Commission, Lorenzo-Martín, L. Francisco, Fernández-Parejo, Natalia, Menacho-Márquez, Mauricio, Rodríguez-Fdez, Sonia, Robles-Valero, Javier, Zumalave, Sonia, Salvatore, Fabbiano, Pascual, Gloria, García-Pedrero, Juana María, Abad, Antonio, García-Macías, Carmen, González, Nazareno, Lorenzano Menna, Pablo, Pavón, Miguel A., González-Sarmiento, Rogelio, Segrelles, Carmen, Paramio, Jesús M., Tubío, José M. C., Rodrigo, Juan Pablo, Benitah, Salvador A., Cuadrado, Myriam, and Bustelo, Xosé R.

Abstract

Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma (hnSCC). However, the pathways that regulate them remain ill-characterized. Here, we show that those traits can be triggered by the RHO GTPase activator VAV2 in keratinocytes present in the skin and oral mucosa. VAV2 is also required to maintain those traits in hnSCC patient-derived cells. This function, which is both catalysis- and RHO GTPase-dependent, is mediated by c-Myc- and YAP/TAZ-dependent transcriptomal programs associated with regenerative proliferation and cell undifferentiation, respectively. High levels of VAV2 transcripts and VAV2-regulated gene signatures are both associated with poor hnSCC patient prognosis. These results unveil a druggable pathway linked to the malignancy of specific SCC subtypes.

Published
2020

23. Vav2 pharmaco-mimetic mice reveal the therapeutic value and caveats of the catalytic inactivation of a Rho exchange factor

Author

Worldwide Cancer Research, Junta de Castilla y León, Ministerio de Ciencia, Innovación y Universidades (España), Asociación Española Contra el Cáncer, Agencia Estatal de Investigación (España), European Commission, Lorenzo-Martín, L. Francisco, Rodríguez-Fdez, Sonia, Fabbiano, Salvatore, Abad, Antonio, García-Macías, Carmen, Dosil, Mercedes, Cuadrado, Myriam, Robles-Valero, Javier, Bustelo, Xosé R., Worldwide Cancer Research, Junta de Castilla y León, Ministerio de Ciencia, Innovación y Universidades (España), Asociación Española Contra el Cáncer, Agencia Estatal de Investigación (España), European Commission, Lorenzo-Martín, L. Francisco, Rodríguez-Fdez, Sonia, Fabbiano, Salvatore, Abad, Antonio, García-Macías, Carmen, Dosil, Mercedes, Cuadrado, Myriam, Robles-Valero, Javier, and Bustelo, Xosé R.

Abstract

The current paradigm holds that the inhibition of Rho guanosine nucleotide exchange factors (GEFs), the enzymes that stimulate Rho GTPases, can be a valuable therapeutic strategy to treat Rho-dependent tumors. However, formal validation of this idea using in vivo models is still missing. In this context, it is worth remembering that many Rho GEFs can mediate both catalysis-dependent and independent responses, thus raising the possibility that the inhibition of their catalytic activities might not be sufficient per se to block tumorigenic processes. On the other hand, the inhibition of these enzymes can trigger collateral side effects that could preclude the practical implementation of anti-GEF therapies. To address those issues, we have generated mouse models to mimic the effect of the systemic application of an inhibitor for the catalytic activity of the Rho GEF Vav2 at the organismal level. Our results indicate that lowering the catalytic activity of Vav2 below specific thresholds is sufficient to block skin tumor initiation, promotion, and progression. They also reveal that the negative side effects typically induced by the loss of Vav2 can be bypassed depending on the overall level of Vav2 inhibition achieved in vivo. These data underscore the pros and cons of anti-Rho GEF therapies for cancer treatment. They also support the idea that Vav2 could represent a viable drug target.

Published
2020

24. Study of genetic factors determining the heterogeneous activation of signaling pathways associated with cardiac pathophysiology and their contribution to the individual susceptibility to cardiotoxicity caused by chemotherapy

Author

Gómez-Vecino, Aurora, Corchado, Juan M., Fraile, Susana, García-Macías, Carmen, and Isidoro-García, María

Abstract

Resumen del póster presentado al XXXIX Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Salamanca del 5 al 8 de septiembre de 2016., The cardiotoxicity of anthracyclines is a complex trait. The degree of cardiac damage is in part mediated by an imbalance between different intracellular signaling pathways such as p38MAPK or PI3K / AKT which at the same time, have been described as being important in other processes of cardiac tissue. Working hypothesis: (i) Interindividual differences in cardiac levels of signaling pathways may contribute to the different susceptibility among patients to cardiac damage produced by anthracyclines (ii) Identification of genomic regions associated with different levels of these signaling proteins is a strategy to identify part of the genetic component of cardiotoxicity. [Material and methods]: We studied a cohort of mice with ERBB2 + breast cancer generated by a backcross between two syngeneic strains, C56BL/6 and FVB (carrier of the transgene MMTV-ErbB2 / Neu). The animals were treated with doxorubicin alone or in combination with docetaxel. Histopathological parameters of cardiac damage were quantified using the Ariol automated system. Levels of the following proteins were quantified by Luminex: pCREB (Ser133), pAKT (Ser473), pSTAT5A / B (Tyr694 / Tyr699), pSTAT3 (Ser707), p70S6K (Thr412), p38 MAPK (Thr180 / Tyr182), pJNK (Thr183 / Tyr185), NFKB (Ser536) and pERK1 / 2 (Thr185 / Tyr187). [Results]: (i) The genetic background influences the activation of heart intracellular signaling pathways. (ii) The levels of activation of these pathways are correlated with histopathological parameters of heart damage. (iii) There are specific and common genetic regions of susceptibility of complex trait (QTL) associated with both processes. [Conclusion]: We used the levels of different intramyocardial signaling pathways as intermediate phenotypes for the identification of part of the genetic component of susceptibility to heart damage caused by chemotherapy. These results will require further validation to be later transferred to the human population.

Published
2016

25. Analysis of genetic and phenotypic interactions between DNA damage / genotoxicity pathways in heart tissue and heart damage caused by anthracyclines and taxanes

Author

Corchado Cobos, Roberto, Gómez-Vecino, Aurora, García-Macías, Carmen, Rodrigues Teixeira, Telmo, Isidoro-García, María, García Sánchez, Asunción, Galvis-Jiménez, Julie Milena, Ramos, Isabel, Blanco-Gómez, Adrián, Sánchez-Fernández, Pedro Luis, and Pérez-Losada, J.

Abstract

Resumen del póster presentado al XXXIX Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Salamanca del 5 al 8 de septiembre de 2016., [Introduction]: Anthracyclines are among the most widely used chemotherapeutic agents in the treatment of a variety of tumors. The identification of genetic and molecular factors responsible for the increased risk of CDA (cardiotoxicity due to anthracyclines) will contribute to a better understanding of their pathophysiology, which could lead to new approaches to predict, prevent and treat this serious complication of chemotherapy. [Working hypothesis]: Based on two premises: (i) anthracyclines have a pro-genotoxicity effect. Differences in anti-genotoxicity pathways and genetic variants could contribute to different susceptibility to CDA. (ii) The usefulness of a simplified model system to identify genetic determinants involved in the quantitative inheritance of complex traits. [Materials and methods]: We treated a cohort of mice carrying ERBB2 breast cancer with doxorubicin alone (N = 85) or in combination with docetaxel (N = 77). The cohort was generated by a backcross between two genetically homogeneous strains, C57BL/6 and FVB, with the latter carrying the MMTV- ErbB2 / Neu transgene. Histopathologic heart damage was assessed by quantification of histologic parameters using Ariol automated system. Cardiac level of some key anti-genotoxicity proteins: ATR total, pp53 (Ser15), P21 Total, Total MDM2, pHistone H2AX (Ser139), pCHK1 (Ser345) and pCHK2 (Thr68) were quantified. [Results]: We identified: (i) differences dependent on the genetic background in both cardiotoxicity and the levels of proteins implicated in the pathways protecting against genotoxicity; (ii) activation of anti-genotoxicity pathways were associated with chemotherapy cardiotoxicity; (iii) quantitative trait loci (QTLs) specific and common to cardiotoxicity and the levels of the pathways studied. [Conclusion]: We identified genetic determinants associated with anthracycline cardiotoxicity using components of the anti-genotoxic pathways as subphenotypes. Crosses of syngeneic mouse strains are useful in these studies, but require further validation in the human population.

Published
2016

26. Immunosuppression-independent role of regulatory T cells against hypertension-driven renal dysfunctions

Author

Junta de Castilla y León, Worldwide Cancer Research, Fundación Memoria de D. Samuel Solorzano Barruso, Fundación Ramón Areces, Consejo Superior de Investigaciones Científicas (España), European Commission, Ministerio de Economía y Competitividad (España), Fabbiano, Salvatore, Menacho-Márquez, Mauricio, Robles-Valero, Javier, Pericacho, Miguel, Matesanz-Marín, Adela, García-Macías, Carmen, Sevilla, Mª Ángeles, Montero, María J., Alarcón, Balbino, López-Novoa, José M., Martín, Pilar, Bustelo, Xosé R., Junta de Castilla y León, Worldwide Cancer Research, Fundación Memoria de D. Samuel Solorzano Barruso, Fundación Ramón Areces, Consejo Superior de Investigaciones Científicas (España), European Commission, Ministerio de Economía y Competitividad (España), Fabbiano, Salvatore, Menacho-Márquez, Mauricio, Robles-Valero, Javier, Pericacho, Miguel, Matesanz-Marín, Adela, García-Macías, Carmen, Sevilla, Mª Ángeles, Montero, María J., Alarcón, Balbino, López-Novoa, José M., Martín, Pilar, and Bustelo, Xosé R.

Abstract

Hypertension-associated cardiorenal diseases represent one of the heaviest burdens for current health systems. In addition to hemodynamic damage, recent results have revealed that hematopoietic cells contribute to the development of these diseases by generating proinflammatory and profibrotic environments in the heart and kidney. However, the cell subtypes involved remain poorly characterized. Here we report that CD39+ regulatory T (TREG) cells utilize an immunosuppression-independent mechanism to counteract renal and possibly cardiac damage during angiotensin II (AngII)-dependent hypertension. This mechanism relies on the direct apoptosis of tissue-resident neutrophils by the ecto-ATP diphosphohydrolase activity of CD39. In agreement with this, experimental and genetic alterations in TREG/TH cell ratios have a direct impact on tissue-resident neutrophil numbers, cardiomyocyte hypertrophy, cardiorenal fibrosis, and, to a lesser extent, arterial pressure elevation during AngII-driven hypertension. These results indicate that TREG cells constitute a first protective barrier against hypertension-driven tissue fibrosis and, in addition, suggest new therapeutic avenues to prevent hypertension-linked cardiorenal diseases.

Published
2015

27. Immunosuppression-Independent Role of Regulatory T Cells against Hypertension-Driven Renal Dysfunctions

Author

Fabbiano, Salvatore, primary, Menacho-Márquez, Mauricio, additional, Robles-Valero, Javier, additional, Pericacho, Miguel, additional, Matesanz-Marín, Adela, additional, García-Macías, Carmen, additional, Sevilla, María A., additional, Montero, M. J., additional, Alarcón, Balbino, additional, López-Novoa, José M., additional, Martín, Pilar, additional, and Bustelo, Xosé R., additional

Published
2015
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30. Intermediate molecular phenotypes to identify genetic markers of anthracycline-induced cardiotoxicity risk.

Author

Gómez-Vecino A, Corchado-Cobos R, Blanco-Gómez A, García-Sancha N, Castillo-Lluva S, Martín-García A, Mendiburu-Eliçabe M, Prieto C, Ruiz-Pinto S, Pita G, Velasco-Ruiz A, Patino-Alonso C, Galindo-Villardón P, Vera-Pedrosa ML, Jalife J, Mao JH, de Plasencia GM, Castellanos-Martín A, Freire MDMS, Fraile-Martín S, Rodrigues-Teixeira T, García-Macías C, Galvis-Jiménez JM, García-Sánchez A, Isidoro-García M, Fuentes M, García-Cenador MB, García-Criado FJ, García JL, Hernández-García MÁ, Hernández JJC, Rodríguez-Sánchez CA, Martín-Ruiz A, Pérez-López E, Pérez-Martínez A, Gutiérrez-Larraya F, Cartón AJ, García-Sáenz JÁ, Patiño-García A, Martín M, Gordoa TA, Vulsteke C, Croes L, Hatse S, Brussel TV, Lambrechts D, Wildiers H, Hang C, Holgado-Madruga M, González-Neira A, Sánchez PL, and Losada JP

Abstract

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex disease whose polygenic component is mainly unidentified. We propose that levels of intermediate molecular phenotypes in the myocardium associated with histopathological damage could explain CDA susceptibility; so that variants of genes encoding these intermediate molecular phenotypes could identify patients susceptible to this complication. A genetically heterogeneous cohort of mice generated by backcrossing (N = 165) was treated with doxorubicin and docetaxel. Cardiac histopathological damage was measured by fibrosis and cardiomyocyte size by an Ariol slide scanner. We determine intramyocardial levels of intermediate molecular phenotypes of CDA associated with histopathological damage and quantitative trait loci (ipQTLs) linked to them. These ipQTLs seem to contribute to the missing heritability of CDA because they improve the heritability explained by QTL directly linked to CDA (cda-QTLs) through genetic models. Genes encoding these molecular subphenotypes were evaluated as genetic markers of CDA in three cancer patient cohorts (N = 517) whose cardiac damage was quantified by echocardiography or Cardiac Magnetic Resonance. Many SNPs associated with CDA were found using genetic models. LASSO multivariate regression identified two risk score models, one for pediatric cancer patients and the other for women with breast cancer. Molecular intermediate phenotypes associated with heart damage can identify genetic markers of CDA risk, thereby allowing a more personalized patient management. A similar strategy could be applied to identify genetic markers of other complex trait diseases.

Published
2023
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31. [Study of AZF regions of Y chromosome in males with idiopathic infertility. Analysis of two methods of molecular diagnosis].

Author

Isidoro-García M, González-Sarmiento R, Cordero M, García-Macías C, Corrales-Hernández JJ, and Miralles-García JM

Subjects
Gene Deletion, Genetic Loci, Humans, Infertility, Male diagnosis, Male, Molecular Diagnostic Techniques, Chromosomes, Human, Y genetics, Infertility, Male genetics, Seminal Plasma Proteins genetics
Abstract

Background and Objective: It is well known that both azoospermia and oligozoospermia are associated to microdeletions of single tagged sites (STS) in the long arm of the Y chromosome. Characterization of deletions is carried out by polymerase chain reaction, although the number and regions included in the analysis varies between laboratories. The aim of this study was to analyze the presence of chromosome Y microdeletions using 2 different sets of STSs., Patients and Method: We analysed the presence of microdeletions in the Yq chromosome in 30 patients with idiopathic male infertility, using 2 sets of STSs, those proposed by the European Molecular Genetics Quality Network (EMQN) as first choice and those of the Y Chromosome Deletion Detection System (Promega)., Results: AZF microdeletions were detected in 4 patients (13%). Only one case was detected simultaneously with both sets., Conclusion: In patients with idiopathic male infertility detection of AZF microdeletion in Y chromosome has important methodological problems. Further studies are needed to achieve a more reliable method to be used by clinical laboratories.

Published
2005
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