General Biochemistry, Genetics and Molecular Biology, Cancer Research, Genetics, Molecular Medicine
28
Scopus Publications
5990
Scholar Citations
27
Scholar h-index
27
Scholar i10-index
Scopus Publications
Questions and answers in the management of children with medulloblastoma over the time. How did we get here? A systematic review Marta P. Osuna-Marco, Laura I. Martín-López, Águeda M. Tejera, Blanca López-Ibor Frontiers in Oncology, 2023 IntroductionTreatment of children with medulloblastoma (MB) includes surgery, radiation therapy (RT) and chemotherapy (CT). Several treatment protocols and clinical trials have been developed over the time to maximize survival and minimize side effects.MethodsWe performed a systematic literature search in May 2023 using PubMed. We selected all clinical trials articles and multicenter studies focusing on MB. We excluded studies focusing exclusively on infants, adults, supratentorial PNETs or refractory/relapsed tumors, studies involving different tumors or different types of PNETs without differentiating survival, studies including <10 cases of MB, solely retrospective studies and those without reference to outcome and/or side effects after a defined treatment.Results1. The main poor-prognosis factors are: metastatic disease, anaplasia, MYC amplification, age younger than 36 months and some molecular subgroups. The postoperative residual tumor size is controversial.2. MB is a collection of diseases.3. MB is a curable disease at diagnosis, but survival is scarce upon relapse.4. Children should be treated by experienced neurosurgeons and in advanced centers.5. RT is an essential treatment for MB. It should be administered craniospinal, early and without interruptions.6. Craniospinal RT dose could be lowered in some low-risk patients, but these reductions should be done with caution to avoid relapses.7. Irradiation of the tumor area instead of the entire posterior fossa is safe enough.8. Hyperfractionated RT is not superior to conventional RT9. Both photon and proton RT are effective.10. CT increases survival, especially in high-risk patients.11. There are multiple drugs effective in MB. The combination of different drugs is appropriate management.12. CT should be administered after RT.13. The specific benefit of concomitant CT to RT is unknown.14. Intensified CT with stem cell rescue has no benefit compared to standard CT regimens.15. The efficacy of intraventricular/intrathecal CT is controversial.16. We should start to think about incorporating targeted therapies in front-line treatment.17. Survivors of MB still have significant side effects.ConclusionSurvival rates of MB improved greatly from 1940-1970, but since then the improvement has been smaller. We should consider introducing targeted therapy as front-line therapy.
Ten Reasons Why People With Down Syndrome are Protected From the Development of Most Solid Tumors -A Review Marta Pilar Osuna-Marco, Mónica López-Barahona, Blanca López-Ibor, Águeda Mercedes Tejera Frontiers in Genetics, 2021 People with Down syndrome have unique characteristics as a result of the presence of an extra chromosome 21. Regarding cancer, they present a unique pattern of tumors, which has not been fully explained to date. Globally, people with Down syndrome have a similar lifetime risk of developing cancer compared to the general population. However, they have a very increased risk of developing certain tumors (e.g., acute leukemia, germ cell tumors, testicular tumors and retinoblastoma) and, on the contrary, there are some other tumors which appear only exceptionally in this syndrome (e.g., breast cancer, prostate cancer, medulloblastoma, neuroblastoma and Wilms tumor). Various hypotheses have been developed to explain this situation. The genetic imbalance secondary to the presence of an extra chromosome 21 has molecular consequences at several levels, not only in chromosome 21 but also throughout the genome. In this review, we discuss the different proposed mechanisms that protect individuals with trisomy 21 from developing solid tumors: genetic dosage effect, tumor suppressor genes overexpression, disturbed metabolism, impaired neurogenesis and angiogenesis, increased apoptosis, immune system dysregulation, epigenetic aberrations and the effect of different microRNAs, among others. More research into the molecular pathways involved in this unique pattern of malignancies is still needed.
A synthetic mRNA cell reprogramming method using CYCLIN D1 promotes DNA repair, generating improved genetically stable human induced pluripotent stem cells Ana Belén Alvarez-Palomo, Jordi Requena-Osete, Raul Delgado-Morales, Victoria Moreno-Manzano, Carme Grau-Bove, Agueda M. Tejera, Manel Juan Otero, Carme Barrot, Irene Santos-Barriopedro, Alejandro Vaquero, Jovita Mezquita-Pla, Sebastian Moran, Carlos Hobeich Naya, Iris Garcia-Martínez, Francisco Vidal Pérez, María A. Blasco, Manel Esteller, Michael J. Edel Stem Cells, 2021 A key challenge for clinical application of induced pluripotent stem cells (iPSC) to accurately model and treat human pathologies depends on developing a method to generate genetically stable cells to reduce long-term risks of cell transplant therapy. Here, we hypothesized that CYCLIN D1 repairs DNA by highly efficient homologous recombination (HR) during reprogramming to iPSC that reduces genetic instability and threat of neoplastic growth. We adopted a synthetic mRNA transfection method using clinically compatible conditions with CYCLIN D1 plus base factors (OCT3/4, SOX2, KLF4, LIN28) and compared with methods that use C-MYC. We demonstrate that CYCLIN D1 made iPSC have (a) lower multitelomeric signal, (b) reduced double-strand DNA breaks, (c) correct nuclear localization of RAD51 protein expression, and (d) reduced single-nucleotide polymorphism (SNP) changes per chromosome, compared with the classical reprogramming method using C-MYC. CYCLIN D1 iPSC have reduced teratoma Ki67 cell growth kinetics and derived neural stem cells successfully engraft in a hostile spinal cord injury (SCI) microenvironment with efficient survival, differentiation. We demonstrate that CYCLIN D1 promotes double-stranded DNA damage repair predominantly through HR during cell reprogramming to efficiently produce iPSC. CYCLIN D1 reduces general cell stress associated with significantly lower SIRT1 gene expression and can rescue Sirt1 null mouse cell reprogramming. In conclusion, we show synthetic mRNA transfection of CYCLIN D1 repairs DNA during reprogramming resulting in significantly improved genetically stable footprint in human iPSC, enabling a new cell reprogramming method for more accurate and reliable generation of human iPSC for disease modeling and future clinical applications.
AAV9-mediated telomerase activation does not accelerate tumorigenesis in the context of oncogenic K-Ras-induced lung cancer Miguel A. Muñoz-Lorente, Paula Martínez, Águeda Tejera, Kurt Whittemore, Ana Carolina Moisés-Silva, Fàtima Bosch, Maria A. Blasco Plos Genetics, 2018 Short and dysfunctional telomeres are sufficient to induce a persistent DNA damage response at chromosome ends, which leads to the induction of senescence and/or apoptosis and to various age-related conditions, including a group of diseases known as “telomere syndromes”, which are provoked by extremely short telomeres owing to germline mutations in telomere genes. This opens the possibility of using telomerase activation as a potential therapeutic strategy to rescue short telomeres both in telomere syndromes and in age-related diseases, in this manner maintaining tissue homeostasis and ameliorating these diseases. In the past, we generated adeno-associated viral vectors carrying the telomerase gene (AAV9-Tert) and shown their therapeutic efficacy in mouse models of cardiac infarct, aplastic anemia, and pulmonary fibrosis. Although we did not observe increased cancer incidence as a consequence of Tert overexpression in any of those models, here we set to test the safety of AAV9-mediated Tert overexpression in the context of a cancer prone mouse model, owing to expression of oncogenic K-ras. As control, we also treated mice with AAV9 vectors carrying a catalytically inactive form of Tert, known to inhibit endogenous telomerase activity. We found that overexpression of Tert does not accelerate the onset or progression of lung carcinomas, even when in the setting of a p53-null background. These findings indicate that telomerase activation by using AAV9-mediated Tert gene therapy has no detectable cancer-prone effects in the context of oncogene-induced mouse tumors.
Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres Juan Manuel Povedano, Paula Martinez, Rosa Serrano, Águeda Tejera, Gonzalo Gómez-López, Maria Bobadilla, Juana Maria Flores, Fátima Bosch, Maria A Blasco Elife, 2018 Pulmonary fibrosis is a fatal lung disease characterized by fibrotic foci and inflammatory infiltrates. Short telomeres can impair tissue regeneration and are found both in hereditary and sporadic cases. We show here that telomerase expression using AAV9 vectors shows therapeutic effects in a mouse model of pulmonary fibrosis owing to a low-dose bleomycin insult and short telomeres. AAV9 preferentially targets regenerative alveolar type II cells (ATII). AAV9-Tert-treated mice show improved lung function and lower inflammation and fibrosis at 1–3 weeks after viral treatment, and improvement or disappearance of the fibrosis at 8 weeks after treatment. AAV9-Tert treatment leads to longer telomeres and increased proliferation of ATII cells, as well as lower DNA damage, apoptosis, and senescence. Transcriptome analysis of ATII cells confirms downregulation of fibrosis and inflammation pathways. We provide a proof-of-principle that telomerase activation may represent an effective treatment for pulmonary fibrosis provoked or associated with short telomeres.
Generation of mice with longer and better preserved telomeres in the absence of genetic manipulations Elisa Varela, Miguel A. Muñoz-Lorente, Agueda M. Tejera, Sagrario Ortega, Maria A. Blasco Nature Communications, 2016 Although telomere length is genetically determined, mouse embryonic stem (ES) cells with telomeres of twice the normal size have been generated. Here, we use such ES cells with ‘hyper-long’ telomeres, which also express green fluorescent protein (GFP), to generate chimaeric mice containing cells with both hyper-long and normal telomeres. We show that chimaeric mice contain GFP-positive cells in all mouse tissues, display normal tissue histology and normal survival. Both hyper-long and normal telomeres shorten with age, but GFP-positive cells retain longer telomeres as mice age. Chimaeric mice with hyper-long telomeres also accumulate fewer cells with short telomeres and less DNA damage with age, and express lower levels of p53. In highly renewing compartments, such as the blood, cells with hyper-long telomeres are longitudinally maintained or enriched with age. We further show that wound-healing rates in the skin are increased in chimaeric mice. Our work demonstrates that mice with functional, longer and better preserved telomeres can be generated without the need for genetic manipulations, such as TERT overexpression.
ATRX driver mutation in a composite malignant pheochromocytoma Iñaki Comino-Méndez, Águeda M. Tejera, María Currás-Freixes, Laura Remacha, Pablo Gonzalvo, Raúl Tonda, Rocío Letón, María A. Blasco, Mercedes Robledo, Alberto Cascón Cancer Genetics, 2016
Localization-dependent and -independent roles of SLX4 in regulating telomeres Jamie S.J. Wilson, Agueda M. Tejera, Dennis Castor, Rachel Toth, Maria A. Blasco, John Rouse Cell Reports, 2013 SLX4, a scaffold for structure-specific DNA repair nucleases, is important for several types of DNA repair. Many repair proteins bind to sites of DNA damage, resulting in subnuclear "foci," but SLX4 forms foci in human cells even without DNA damage. Using several approaches, we show that most, but not all, SLX4 foci localize to telomeres in a range of human cell lines irrespective of the mechanisms used to maintain telomere length. The SLX1 Holliday-junction-processing enzyme is recruited to telomeres by SLX4, and SLX4, in turn, is recruited by a motif that binds to the shelterin subunit TRF2 directly. We also show that TRF2-dependent recruitment of SLX4 prevents telomere damage. Furthermore, SLX4 prevents telomere lengthening and fragility in a manner that appears to be independent of telomere association. These findings reveal that SLX4 plays multiple roles in regulating telomere homeostasis.
Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer Bruno Bernardes de Jesus, Elsa Vera, Kerstin Schneeberger, Agueda M. Tejera, Eduard Ayuso, Fatima Bosch, Maria A. Blasco EMBO Molecular Medicine, 2012 A major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of 1‐ and 2‐year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging. Importantly, telomerase‐treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors. Finally, telomerase‐treated mice, both at 1‐year and at 2‐year of age, had an increase in median lifespan of 24 and 13%, respectively. These beneficial effects were not observed with a catalytically inactive TERT, demonstrating that they require telomerase activity. Together, these results constitute a proof‐of‐principle of a role of TERT in delaying physiological aging and extending longevity in normal mice through a telomerase‐based treatment, and demonstrate the feasibility of anti‐aging gene therapy.See accompanying article http://dx.doi.org/10.1002/emmm.201200246
Telomerase Reverse Transcriptase Delays Aging in Cancer-Resistant Mice Antonia Tomás-Loba, Ignacio Flores, Pablo J. Fernández-Marcos, María L. Cayuela, Antonio Maraver, Agueda Tejera, Consuelo Borrás, Ander Matheu, Peter Klatt, Juana M. Flores, José Viña, Manuel Serrano, Maria A. Blasco Cell, 2008
Differential Microrna Expression in Medulloblastoma: A Focus on Chromosome 21 M Osuna-Marco, E Galian-Gevara, B Lopez-Ibor, A Tejera PEDIATRIC BLOOD & CANCER 72, S403-S403 , 2025 2025
STUDY OF THE ANTIPROLIFERATIVE EFFECT OF POLYPHENOLS FROM GRAPE MUST ON PEDIATRIC TUMORS SG Arconada, AM Fernandez, DG Martinez, CS Tejedor, AM Tejera PEDIATRIC BLOOD & CANCER 70 , 2023 2023
Questions and answers in the management of children with medulloblastoma over the time. How did we get here? A systematic review MP Osuna-Marco, LI Martin-Lopez, AM Tejera, B Lopez-Ibor Frontiers in Oncology 13, 1229853 , 2023 2023 Citations: 6
UNIQUE PATTERN OF CANCER DEVELOPMENT IN PEOPLE WITH DOWN SYNDROME MO Marco, A Tejera, B Lopez-Ibor PEDIATRIC BLOOD & CANCER 69, S632-S633 , 2022 2022
Emprendimiento medioambiental: aprendizaje mediante proyectos transversales en el Grado de Biotecnología ÁM Tejera, AB Esteban, RF de Caleya Innovación educativa para el desarrollo sostenible, la economía y la empresa … , 2022 2022
Ten reasons why people with down syndrome are protected from the development of most solid tumors-a review MP Osuna-Marco, M López-Barahona, B López-Ibor, ÁM Tejera Frontiers in genetics 12, 749480 , 2021 2021 Citations: 39
A Synthetic mRNA Cell Reprogramming Method Using CYCLIN D1 Promotes DNA rEpair, Generating Improved Genetically Stable Human Induced Pluripotent … AB Alvarez-Palomo, J Requena-Osete, R Delgado-Morales, ... Stem Cells 39 (7), 866-881 , 2021 2021 Citations: 28
A synthetic mRNA cell reprogramming method using CYCLIN D1 promotes DNA repair, generating improved genetically stable human induced pluripotent stem cells Stem Cells 39 (7), 866-881 , 2021 2021
AAV9-mediated telomerase activation does not accelerate tumorigenesis in the context of oncogenic K-Ras-induced lung cancer MA Muñoz-Lorente, P Martínez, Á Tejera, K Whittemore, AC Moisés-Silva, ... PLoS genetics 14 (8), e1007562 , 2018 2018 Citations: 38
Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres JM Povedano Selfa, P Martinez Rodriguez, R Serrano Ruiz, A Tejera, ... eLife Sciences Publications , 2018 2018
Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres JM Povedano, P Martinez, R Serrano, Á Tejera, G Gómez-López, ... Elife 7, e31299 , 2018 2018 Citations: 157
Generation of mice with longer and better preserved telomeres in the absence of genetic manipulations E Varela, MA Muñoz-Lorente, AM Tejera, S Ortega, MA Blasco Nature communications 7, 11739 , 2016 2016 Citations: 79
ATRX driver mutation in a composite malignant pheochromocytoma I Comino-Méndez, ÁM Tejera, M Currás-Freixes, L Remacha, P Gonzalvo, ... Cancer Genetics 209 (6), 272-277 , 2016 2016 Citations: 29
Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction C Bär, BB De Jesus, R Serrano, A Tejera, E Ayuso, V Jimenez, ... Nature communications 5, 5863 , 2014 2014 Citations: 190
Localization-dependent and-independent roles of SLX4 in regulating telomeres JSJ Wilson, AM Tejera, D Castor, R Toth, MA Blasco, J Rouse Cell reports 4 (5), 853-860 , 2013 2013 Citations: 110
Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer BB de Jesus, E Vera, K Schneeberger, AM Tejera, E Ayuso, F Bosch, ... EMBO molecular medicine 4 (8), 691-704 , 2012 2012 Citations: 763
The telomerase activator TA‐65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence BB de Jesus, K Schneeberger, E Vera, A Tejera, CB Harley, MA Blasco Aging cell 10 (4), 604-621 , 2011 2011 Citations: 321
The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. B Bernardes de Jesus, K Schneeberger, E Vera, A Tejera, CB Harley, ... Aging cell 10 (4), 604-621 , 2011 2011 Citations: 208
Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites P Martinez, M Thanasoula, AR Carlos, G Gómez-López, AM Tejera, ... Nature cell biology 12 (8), 768-780 , 2010 2010 Citations: 345
TPP1 is required for TERT recruitment, telomere elongation during nuclear reprogramming, and normal skin development in mice AM Tejera, MS d'Alcontres, M Thanasoula, RM Marion, P Martinez, C Liao, ... Developmental cell 18 (5), 775-789 , 2010 2010 Citations: 173
MOST CITED SCHOLAR PUBLICATIONS
Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer BB de Jesus, E Vera, K Schneeberger, AM Tejera, E Ayuso, F Bosch, ... EMBO molecular medicine 4 (8), 691-704 , 2012 2012 Citations: 763
Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells RM Marion, K Strati, H Li, A Tejera, S Schoeftner, S Ortega, M Serrano, ... Cell stem cell 4 (2), 141-154 , 2009 2009 Citations: 651
Telomerase reverse transcriptase delays aging in cancer-resistant mice A Tomás-Loba, I Flores, PJ Fernandez-Marcos, ML Cayuela, A Maraver, ... Cell 135 (4), 609-622 , 2008 2008 Citations: 644
Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice P Martínez, M Thanasoula, P Muñoz, C Liao, A Tejera, C McNees, ... Genes & development 23 (17), 2060-2075 , 2009 2009 Citations: 470
The longest telomeres: a general signature of adult stem cell compartments I Flores, A Canela, E Vera, A Tejera, G Cotsarelis, MA Blasco Genes & development 22 (5), 654-667 , 2008 2008 Citations: 444
Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites P Martinez, M Thanasoula, AR Carlos, G Gómez-López, AM Tejera, ... Nature cell biology 12 (8), 768-780 , 2010 2010 Citations: 345
The telomerase activator TA‐65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence BB de Jesus, K Schneeberger, E Vera, A Tejera, CB Harley, MA Blasco Aging cell 10 (4), 604-621 , 2011 2011 Citations: 321
A G-quadruplex ligand with 10000-fold selectivity over duplex DNA IM Dixon, F Lopez, AM Tejera, JP Estève, MA Blasco, G Pratviel, ... Journal of the American Chemical Society 129 (6), 1502-1503 , 2007 2007 Citations: 291
The copper‐chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells J Yoshii, H Yoshiji, S Kuriyama, Y Ikenaka, R Noguchi, H Okuda, ... International journal of cancer 94 (6), 768-773 , 2001 2001 Citations: 221
The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. B Bernardes de Jesus, K Schneeberger, E Vera, A Tejera, CB Harley, ... Aging cell 10 (4), 604-621 , 2011 2011 Citations: 208
Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction C Bär, BB De Jesus, R Serrano, A Tejera, E Ayuso, V Jimenez, ... Nature communications 5, 5863 , 2014 2014 Citations: 190
Porphyrin derivatives for telomere binding and telomerase inhibition IM Dixon, F Lopez, JP Estève, AM Tejera, MA Blasco, G Pratviel, ... ChemBioChem 6 (1), 123-132 , 2005 2005 Citations: 187
TPP1 is required for TERT recruitment, telomere elongation during nuclear reprogramming, and normal skin development in mice AM Tejera, MS d'Alcontres, M Thanasoula, RM Marion, P Martinez, C Liao, ... Developmental cell 18 (5), 775-789 , 2010 2010 Citations: 173
Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres JM Povedano, P Martinez, R Serrano, Á Tejera, G Gómez-López, ... Elife 7, e31299 , 2018 2018 Citations: 157
Irreversible telomere shortening by 3′-azido-2′, 3′-dideoxythymidine (AZT) treatment DE Gomez, AM Tejera, OA Olivero Biochemical and biophysical research communications 246 (1), 107-110 , 1998 1998 Citations: 145
Localization-dependent and-independent roles of SLX4 in regulating telomeres JSJ Wilson, AM Tejera, D Castor, R Toth, MA Blasco, J Rouse Cell reports 4 (5), 853-860 , 2013 2013 Citations: 110
Expression of mTert in primary murine cells links the growth-promoting effects of telomerase to transforming growth factor-β signaling C Geserick, A Tejera, E Gonzalez-Suarez, P Klatt, MA Blasco Oncogene 25 (31), 4310-4319 , 2006 2006 Citations: 94
ATR suppresses telomere fragility and recombination but is dispensable for elongation of short telomeres by telomerase CJ McNees, AM Tejera, P Martínez, M Murga, F Mulero, ... The Journal of cell biology 188 (5), 639-652 , 2010 2010 Citations: 89
Zidovudine induces S-phase arrest and cell cycle gene expression changes in human cells OA Olivero, AM Tejera, JJ Fernandez, BJ Taylor, S Das, RL Divi, ... Mutagenesis 20 (2), 139-146 , 2005 2005 Citations: 80
Generation of mice with longer and better preserved telomeres in the absence of genetic manipulations E Varela, MA Muñoz-Lorente, AM Tejera, S Ortega, MA Blasco Nature communications 7, 11739 , 2016 2016 Citations: 79
