Lujambio, A. (Amaya)
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- Activation of the unfolded protein response (UPR) is associated with cholangiocellular injury, fibrosis and carcinogenesis in an experimental model of fibropolycystic liver disease(2022) Latasa, M.U. (María Ujué); Bañares, R. (Rafael); Berasain, C. (Carmen); Arechederra, M. (María); Fernández-Barrena, M.G. (Maite G.); Nevzorova, Y. (Yulia); Peligros, M.I. (María Isabel); Nelson, L.J. (Leonard J.); Avila, M.A. (Matías Antonio); Davis, R.J. (Roger J.); Tortajada, A. (Agustín); Wu, H. (Hanghang); Vidal, A. (August); Rodriguez-Perales, S. (Sandra); Ye, H. (Hui); Reissing, J. (Johanna); Mohamed, M.R. (Mohamed Ramadan); Iraburu-Elizalde, M. (María); Lujambio, A. (Amaya); Martínez-Naves, E. (Eduardo); Trautwein, C. (Christian); Villanueva, A. (Alberto); Vaquero, J. (Javier); Colyn, L. (Leticia); Torres-Ruiz, R. (Raúl); Zheng, K. (Kang); Bruns, T. (Tony); Cubero, F.J. (Francisco Javier); Chen, C. (Chaobo)Polycystic liver disease (PLD) is a group of rare disorders that result from structural changes in the biliary tree development in the liver. In the present work, we studied alterations in molecular mechanisms and signaling pathways that might be responsible for these pathologies. We found that activation of the unfolded protein response, a process that occurs in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum, as well as the scarring of the liver tissue, contribute to the pathogenesis of PLD and the development of cancer. As a preclinical animal model we have used mutant mice of a specific signaling pathway, the c-Jun N-terminal kinase 1/2 (Jnk1/2). These mice resemble a perfect model for the study of PLD and early cancer development.
- Epigenetic activation of SOX11 in lymphoid neoplasms by histone modifications(Public Library of Science, 2011) Jares, P. (Pedro); Salaverria-Lete, I. (Itziar); Richter, J. (Julia); Roman-Gomez, J. (José); Xargay-Torrent, S. (Silvia); Rosenwald, A. (Andreas); Ott, G. (German); Enjuanes, A. (Anna); Bea, S. (Silvia); Palomero, J. (Jara); Royo, C. (Cristina); Martin-Guerrero, I. (Idoia); Hernandez, L. (Luis); Amador, V. (Virginia); Campo, E. (Elías); Siebert, R. (Reiner); Balint, B. (Balazs); Lujambio, A. (Amaya); Esteller, M. (Manel); Vegliante, M.C. (Maria Carmela); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio)Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications
- Genetic modification of CD8+ T cells to express EGFR: Potential application for adoptive T cell therapies(Frontiers Media SA, 2019) Sarrión, P. (Patricia); Lozano-Moreda, T. (Teresa); Valle, C. (Cynthia) del; Hervas-Stubbs, S. (Sandra); Casares, N. (Noelia); Lujambio, A. (Amaya); Martin, C. (Celia); Sarobe, P. (Pablo); Gorraiz, M. (Marta); Lasarte-Cia, A. (Aritz); Chocarro, S. (Silva); Ruiz-de-Galarreta-Martínez, M. (Marina); Lasarte, J.J. (Juan José)Adoptive immunotherapy with ex vivo-expanded tumor-infiltrating lymphocytes (TILs) has achieved objective clinical responses in a significant number of patients with cancer. The failure of many patients to develop long-term tumor control may be, in part, due to exhaustion of transferred T cells in the presence of a hostile tumor microenvironment. In several tumor types, growth and survival of carcinoma cells appear to be sustained by a network of receptors/ligands of the ErbB family. We speculated that if transferred T cells could benefit from EGFR ligands produced by the tumor, they might proliferate better and exert their anti-tumor activities more efficiently. We found that CD8+ T cells transduced with a retrovirus to express EGFR responded to EGFR ligands activating the EGFR signaling pathway. These EGFR-expressing effector T cells proliferated better and produced more IFN-γ and TNF-α in the presence of EGFR ligands produced by tumor cells in vitro. EGFR-expressing CD8 T cells from OT-1 mice were more efficient killing B16-OVA cells than control OT-1 CD8 T cells. Importantly, EGFR-expressing OT-1 T cells injected into B16-OVA tumor bearing mice were recruited into the tumor, expressed lower levels of the exhaustion markers PD1, TIGIT, and LAG3, and were more efficient in delaying tumor growth. Our results suggest that genetic modification of CD8+ T cells to express EGFR might be considered in immunotherapeutic strategies based on adoptive transfer of anti-tumor T cells against cancers expressing EGFR ligands.
- Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses against Hepatocellular Carcinoma(2020) Egea, J. (Josune); Silva, L. (Leyre); Ruiz, M. (Marta); Sangro, B. (Bruno); Repáraz-Pernaut, D. (David); Lujambio, A. (Amaya); Llopiz, D. (Diana); Sarobe, P. (Pablo); Villanueva, L. (Lorea); Aparicio-De-la-Torre, B. (Belén); Lasarte-Cia, A. (Aritz); Ruiz-de-Galarreta-Martínez, M. (Marina); Lasarte, J.J. (Juan José)Therapies based on immune checkpoint inhibitors (ICPI) have yielded promising albeit limited results in patients with hepatocellular carcinoma (HCC). Vaccines have been proposed as combination partners to enhance response rates to ICPI. Thus, we analyzed the combined effect of a vaccine based on the TLR4 ligand cold-inducible RNA binding protein (CIRP) plus ICPI. Mice were immunized with vaccines containing ovalbumin linked to CIRP (OVA-CIRP), with or without ICPI, and antigen-specific responses and therapeutic efficacy were tested in subcutaneous and orthotopic mouse models of liver cancer. OVA-CIRP elicited polyepitopic T-cell responses, which were further enhanced when combined with ICPI (anti-PD-1 and anti-CTLA-4). Combination of OVA-CIRP with ICPI enhanced ICPI-induced therapeutic responses when tested in subcutaneous and intrahepatic B16-OVA tumors, as well as in the orthotopic PM299L HCC model. This effect was associated with higher OVA-specific T-cell responses in the periphery, although many tumor-infiltrating lymphocytes still displayed an exhausted phenotype. Finally, a new vaccine containing human glypican-3 linked to CIRP (GPC3-CIRP) induced clear responses in humanized HLA-A2.01 transgenic mice, which increased upon combination with ICPI. Therefore, CIRP-based vaccines may generate anti-tumor immunity to enhance ICPI efficacy in HCC, although blockade of additional checkpoint molecules and immunosuppressive targets should be also considered.
- Splicing regulator SLU7 is essential for maintaining liver homeostasis(2014) Latasa, M.U. (María Ujué); Berasain, C. (Carmen); Collantes, M. (María); García-Irigoyen, O. (Oihane); Uriarte, I. (Iker); Avila, M.A. (Matías Antonio); Azkona, M.T. (María Teresa); Goñi, S. (Saioa); Raquel; Prieto, J. (Jesús); Lujambio, A. (Amaya); Elizalde, M. (María); Segura, V. (Víctor); Scala, M. (Marianna) DiA precise equilibrium between cellular differentiation and proliferation is fundamental for tissue homeostasis. Maintaining this balance is particularly important for the liver, a highly differentiated organ with systemic metabolic functions that is endowed with unparalleled regenerative potential. Carcinogenesis in the liver develops as the result of hepatocellular de-differentiation and uncontrolled proliferation. Here, we identified SLU7, which encodes a pre-mRNA splicing regulator that is inhibited in hepatocarcinoma, as a pivotal gene for hepatocellular homeostasis. SLU7 knockdown in human liver cells and mouse liver resulted in profound changes in pre-mRNA splicing and gene expression, leading to impaired glucose and lipid metabolism, refractoriness to key metabolic hormones, and reversion to a fetal-like gene expression pattern. Additionally, loss of SLU7 also increased hepatocellular proliferation and induced a switch to a tumor-like glycolytic phenotype. Slu7 governed the splicing and/or expression of multiple genes essential for hepatocellular differentiation, including serine/arginine-rich splicing factor 3 (Srsf3) and hepatocyte nuclear factor 4α (Hnf4α), and was critical for cAMP-regulated gene transcription. Together, out data indicate that SLU7 is central regulator of hepatocyte identity and quiescence.