Vilas-Zornoza, A. (Amaia)
- Publications
- item.page.relationships.isContributorAdvisorOfPublication
- item.page.relationships.isContributorOfPublication
5 results
Search Results
Now showing 1 - 5 of 5
- Characterization of complete lncRNAs transcriptome reveals the functional and clinical impact of lncRNAs in multiple myeloma.(Springer Nature, 2021) Carrasco-León, A. (Arantxa); Ezponda, T. (Teresa); Meydan, C. (Cem); Valcárcel-García, L.V. (Luis Vitores); Ordoñez, R. (Raquel); Kulis, M. (Marta); Garate, L. (Leire); Miranda, E. (Estibaliz); Segura, V. (Víctor); Guruceaga, E. (Elizabeth); Vilas-Zornoza, A. (Amaia); Alignani, D. (Diego); Pascual, M. (Marien); Amundarain, A. (Ane); Castro-Labrador, L. (Laura); San Martín, P. (Patxi); El-Omri, H. (Halima); Taha, R.Y. (Ruba Y.); Calasanz-Abinzano, M.J. (Maria Jose); Planes-Pedreño, F.J. (Francisco Javier); Paiva, B. (Bruno); Mason, C. E. (Christopher, E.); San-Miguel, J.F. (Jesús F.); Martin-Subero, J.I. (Jose Ignacio); Melnick, A. (Ari); Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier)Multiple myeloma (MM) is an incurable disease, whose clinical heterogeneity makes its management challenging, highlighting the need for biological features to guide improved therapies. Deregulation of specific long non-coding RNAs (lncRNAs) has been shown in MM, nevertheless, the complete lncRNA transcriptome has not yet been elucidated. In this work, we identified 40,511 novel lncRNAs in MM samples. lncRNAs accounted for 82% of the MM transcriptome and were more heterogeneously expressed than coding genes. A total of 10,351 overexpressed and 9,535 downregulated lncRNAs were identified in MM patients when compared with normal bone-marrow plasma cells. Transcriptional dynamics study of lncRNAs in the context of normal B-cell maturation revealed 989 lncRNAs with exclusive expression in MM, among which 89 showed de novo epigenomic activation. Knockdown studies on one of these lncRNAs, SMILO (specific myeloma intergenic long non-coding RNA), resulted in reduced proliferation and induction of apoptosis of MM cells, and activation of the interferon pathway. We also showed that the expression of lncRNAs, together with clinical and genetic risk alterations, stratified MM patients into several progression-free survival and overall survival groups. In summary, our global analysis of the lncRNAs transcriptome reveals the presence of specific lncRNAs associated with the biological and clinical behavior of the disease.
- Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma(2020) García-Torre, B. (Beatriz); Soler-Vila, P. (Paula); Taha, R.Y. (Ruba Y.); Beekman, R. (Renée); Rodriguez-Madoz, J.R. (Juan Roberto); El-Omri, H. (Halima); Charalampopoulou, S. (Stella); San-Jose-Eneriz, E. (Edurne); Martens, J.H.A. (Joost H. A.); Flicek, P. (Paul); Agirre, X. (Xabier); Stunnenberg, H.G. (Hendrik G.); Garate, L. (Leire); Kulis, M. (Marta); Mitsiades, C.S. (Constantine S.); Licht, J.D. (Jonathan D.); Carrasco-León, A. (Arantxa); Chapaprieta, V. (Vicente); Lara-Astiaso, D. (David); Ezponda, T. (Teresa); Ordóñez-Ciriza, R. (Raquel); Verdaguer-Dot, N. (Núria); Vilas-Zornoza, A. (Amaia); Campo, E. (Elías); Dupéré-Richer, D. (Daphné); Miranda, E. (Estibaliz); Duran-Ferrer, M. (Martí); Meydan, C. (Cem); Paiva, B. (Bruno); Vilarrasa-Blasi, R. (Roser); Gut, I. (Ivo); Melnick, A. (Ari); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Martínez-Turrilas, R. (Rebeca); Clot, G. (Guillem); San-Miguel, J.F. (Jesús F.); Martin-Subero, J.I. (Jose Ignacio); Russiñol, N. (Nuria)Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.
- Loss of the matrix metalloproteinase-10 causes premature features of aging in satellite cells(2023) Rodríguez-García, J.A. (José Antonio); Paramo, J.A. (José Antonio); Ullate-Agote, A. (Asier); Bobadilla, M. (Míriam); Machado, F. J. D. (Florencio J.D.); Paradas, C. (Carmen); Vallejo-Illarramendi, A. (Ainara); Orbe, J. (Josune); Ramos, L.I. (Luis Isaac); Baraibar-Churio, A. (Arantxa); Romero-Riojas, J.P. (Juan Pablo); Extramiana, L. (Leire); Cantero, G. (Gloria); Vilas-Zornoza, A. (Amaia); López-de-Munain, A. (Adolfo); Prosper-Cardoso, F. (Felipe); Pérez-Ruiz, A.I. (Ana Isabel); Sainz, N. (Neira); Abizanda-Sarasa, G. (Gloria); Aranguren, X.L. (Xabier L.)Aged muscles accumulate satellite cells with a striking decline response to damage. Although intrinsic defects in satellite cells themselves are the major contributors to aging-associated stem cell dysfunction, increasing evidence suggests that changes in the muscle-stem cell local microenvironment also contribute to aging. Here, we demonstrate that loss of the matrix metalloproteinase-10 (MMP-10) in young mice alters the composition of the muscle extracellular matrix (ECM), and specifically disrupts the extracellular matrix of the satellite cell niche. This situation causes premature features of aging in the satellite cells, contributing to their functional decline and a predisposition to enter senescence under proliferative pressure. Similarly, reduction of MMP-10 levels in young satellite cells from wild type animals induces a senescence response, while addition of the protease delays this program. Significantly, the effect of MMP-10 on satellite cell aging can be extended to another context of muscle wasting, muscular dystrophy. Systemic treatment of mdx dystrophic mice with MMP-10 prevents the muscle deterioration phenotype and reduces cellular damage in the satellite cells, which are normally under replicative pressure. Most importantly, MMP-10 conserves its protective effect in the satellite cell-derived myoblasts isolated from a Duchenne muscular dystrophy patient by decreasing the accumulation of damaged DNA. Hence, MMP-10 provides a previously unrecognized therapeutic opportunity to delay satellite cell aging and overcome satellite cell dysfunction in dystrophic muscles.
- Gene therapy restores the transcriptional program of hematopoietic stem cells in Fanconi anemia(2023) Fernández-Varas, B. (Beatriz); Ainciburi, M. (Marina); Navarro, S. (Susana); Gomez-Cabrero, D. (David); Ullate-Agote, A. (Asier); Lasaga, M. (Miren); Sastre, L. (Leandro); Schwartz, J.D. (Jonathan D.); Nicoletti, E. (Eileen); Pujol, R.M. (Roser M.); Surralles, J. (Jordi); Sevilla, J. (Julián); Planell, N. (Núria); Perona, R. (Rosario); Vilas-Zornoza, A. (Amaia); Alignani, D. (Diego); Mouzo, D. (Daniel); Bueren, J.A. (Juan A.); Prosper-Cardoso, F. (Felipe); Rio, P. (Paula); Zubicaray, J. (Josune)Clinical trials have shown that lentiviral-mediated gene therapy can ameliorate bone marrow failure (BMF) in nonconditioned Fanconi anemia (FA) patients resulting from the proliferative advantage of corrected FA hematopoietic stem and progenitor cells (HSPC). However, it is not yet known if gene therapy can revert affected molecular pathways in diseased HSPC. Single-cell RNA sequencing was performed in chimeric populations of corrected and uncorrected HSPC co-existing in the BM of gene therapy-treated FA patients. Our study demonstrates that gene therapy reverts the transcriptional signature of FA HSPC, which then resemble the transcriptional program of healthy donor HSPC. This includes a down-regulated expression of TGF-ß and p21, typically up-regulated in FA HSPC, and upregulation of DNA damage response and telomere maintenance pathways. Our results show for the first time the potential of gene therapy to rescue defects in the HSPC transcriptional program from patients with inherited diseases; in this case, in FA characterized by BMF and cancer predisposition.
- Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression(2019) Segovia, C. (Cristina); San-Jose-Eneriz, E. (Edurne); Munera-Maravilla, E. (Ester); Martínez-Fernández, M. (Mónica); Garate, L. (Leire); Miranda, E. (Estibaliz); Vilas-Zornoza, A. (Amaia); Lodewijk, I. (Iris); Rubio, C. (Carolina); Segrelles, C. (Carmen); Valcárcel-García, L.V. (Luis Vitores); Rabal, O. (Obdulia); Casares, N. (Noelia); Bernardini, A. (Alejandra); Suárez-Cabrera, C. (Cristian); Lopez-Calderón, F. (Fernando); Fortes, P. (Puri)Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances(1,2). Recent molecular characterization has defined new (epi) genetic drivers and potential targets for bladder cancer(3,4). The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients(5-8). Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (Pten(loxP/loxP); Trp53(loxP/loxP); Rb1(loxP/loxP); Rbl1(-/-)) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.