Suchergebnisse

Idiopathic pulmonary fibrosis (IPF) is a degenerative disease of the lungs with an average survival post-diagnosis of 2-3 years. New therapeutic targets and treatments are necessary. Mutations in components of the telomere-maintenance enzyme telomerase or in proteins important for telomere protection are found in both familial and sporadic IPF cases. However, the lack of mouse models that faithfully recapitulate the human disease has hampered new advances. Here, we generate two independent mouse models that develop IPF owing to either critically short telomeres (telomerase-deficient mice) or severe telomere dysfunction in the absence of telomere shortening (mice with Trf1 deletion in type II alveolar cells). We show that both mouse models develop pulmonary fibrosis through induction of telomere damage, thus providing proof of principle of the causal role of DNA damage stemming from dysfunctional telomeres in IPF development and identifying telomeres as promising targets for new treatments. ; Research in the Blasco lab is funded by the Spanish Ministry of Economy and Competitiveness Projects SAF2008-05384 and CSD2007-00017, the European Union FP7 Projects 2007-A-201630 (GENICA) and 2007-A-200950 (TELOMARKER), the European Research Council (ERC) Project TEL STEM CELL (GA#232854), the Korber Foundation, the AXA Research Fund, Fundacion Botin, and Fundacion Lilly (Spain). F.B. is ICREA Academia, Generalitat de Catalunya, Spain. ; Sí

S.N.-P. and P.J.F.-M. have been funded by the Spanish Association Against Cancer(aecc). Work in the laboratory of M.S. is funded by the CNIO and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund(SAF project), the European Research Council (ERC Advanced Grant), the Regional Government of Madrid co-funded by the European Social Fund (ReCaRe project), the European Union (RISK-IR project), the Botin Foundation and Banco Santander(Santander Universities Global Division), the Ramon Areces Foundation, and the AXA Foundation. Work in the laboratory of J.V. was supported by grants SAF2013-44663-R,from the Spanish Ministry of Education and Science (MEC); ISCIII2012-RED-43-029from RETICEF; PROMETEO2014/056 from "Conselleria d'Educacio , Cultura i Esport de la Generalitat Valenciana"; RS2012-609 Intramural Grant from INCLIVA and EUFunded CM1001 andFRAILOMIC-HEALTH.2012.2.1.1-2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ; Reactive oxygen species (ROS) are constantly generated by cells and ROS-derived damage contributes to ageing. Protection against oxidative damage largely relies on the reductive power of NAPDH, whose levels are mostly determined by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Here, we report a transgenic mouse model with moderate overexpression of human G6PD under its endogenous promoter. Importantly, G6PD-Tg mice have higher levels of NADPH, lower levels of ROS-derived damage, and better protection from ageing-associated functional decline, including extended median lifespan in females. The G6PD transgene has no effect on tumour development, even after combining with various tumour-prone genetic alterations. We conclude that a modest increase in G6PD activity is beneficial for healthspan through increased NADPH levels and protection from the deleterious effects of ROS. ; Sí

Altres ajuts: NM-M was supported by the Spanish Association Against Cancer (AECC), AECC JP Vizcaya. VT is supported by Fundación Vasca de Innovación e Investigación Sanitarias, BIOEF (BIO15/CA/052), the department of health of the Basque Government (2016111109) and the 2016 grant of the AECC (Junta provincial de Bizkaia). LA, AA-A and LV-J were supported by the Basque Government of education. The work of A.C. is supported by the Ramón y Cajal award, the Basque Department of Industry, Tourism and Trade (Etortek) and the department of education (IKERTALDE IT1106-16), FERO VIII Fellowship, the BBVA foundation, Severo Ochoa. Excellence Accreditation SEV-2016-0644) and the European Research Council (Starting Grant 336343; Proof of Concept 754627). The participation of AC, VT, NM-M, SF and AZ as part of CIBERONC was co-funded with FEDER funds. ; Prostate cancer is diagnosed late in life, when co-morbidities are frequent. Among them, hypertension, hypercholesterolemia, diabetes or metabolic syndrome exhibit an elevated incidence. In turn, prostate cancer patients frequently undergo chronic pharmacological treatments that could alter disease initiation, progression and therapy response. Here we show that treatment with anti-cholesterolemic drugs, statins, at doses achieved in patients, enhance the pro-tumorigenic activity of obesogenic diets. In addition, the use of a mouse model of prostate cancer and human prostate cancer xenografts revealed that in vivo simvastatin administration alone increases prostate cancer aggressiveness. In vitro cell line systems supported the notion that this phenomenon occurs, at least in part, through the direct action on cancer cells of low doses of statins, in range of what is observed in human plasma. In sum, our results reveal a prostate cancer experimental system where statins exhibit an undesirable effect, and warrant further research to address the relevance and implications of this observation in human prostate cancer.

Altres ajuts: V. Torrano is funded by Fundación Vasca de Innovación e Investigación Sanitarias, Bioef (BIO15/CA/052), the Fundación Científica Asociación Española Contra el Cáncer J.P. Bizkaia, and the Basque Department of Health (2016111109). The work of A. Carracedo is supported by the Basque Department of Industry, Tourism and Trade (Elkartek), the Department of Education (IKERTALDE IT1106-16, with A. Gomez-Muñoz), the Department of Health (2019222031), the Fundación BBVA, FEDER [European Regional Development Fund, EU]; the Fundación Científica Asociación Española Contra el Cáncer (IDEAS175CARR; GCTRA18006CARR, with M. Graupera and R.R. Gomis), "La Caixa" Foundation (HR17-00094), and the European Research Council (Starting Grant , PoC , and Consolidator Grant 819242). G. Velasco's research is funded by Fundació la Marató de TV3 (20134031). R.R. Gomis is supported by "La Caixa" Foundation (HR17-00092). CIBERONC was cofunded with European Regional Development funds and funded by Instituto de Salud Carlos III. L. Valcarcel-Jimenez was funded by a Basque Government predoctoral grant. ; This study unravels an unprecedented murine model of lethal metastatic prostate cancer, based on the combined deletion of Pten and Lkb1. Importantly, minimal activity of LKB1 is sufficient to hamper prostate cancer cell aggressiveness, thus redefining the relationship between gene dosage and tumor suppression. Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly ...