Anna Tutusaus
Spanish National Research Council
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Featured researches published by Anna Tutusaus.
Journal of Hepatology | 2015
Cristina Bárcena; Milica Stefanovic; Anna Tutusaus; Leonel Joannas; Anghara Menendez; Carmen García-Ruiz; Pau Sancho-Bru; Montserrat Marí; Joan Caballería; Carla V. Rothlin; José C. Fernández-Checa; Pablo García de Frutos; Albert Morales
BACKGROUND & AIMS Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a receptor tyrosine kinase and its ligand Gas6, are involved in cell differentiation, immune response and carcinogenesis. METHODS HSCs were obtained from WT and Axl(-/-) mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl4-treated WT and Axl(-/-) mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients. RESULTS In primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl(-/-) mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. Similarly, BGB324 reduced collagen deposition and CCl4-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality. CONCLUSIONS The Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management.
Oncotarget | 2016
Milica Stefanovic; Anna Tutusaus; Guillermo A. Martínez-Nieto; Cristina Bárcena; Estefanía de Gregorio; Catia Moutinho; Elisabet Barbero-Camps; Alberto Villanueva; Anna Colell; Montserrat Marí; Carmen García-Ruiz; José C. Fernández-Checa; Albert Morales
Evasive mechanisms triggered by the tyrosine kinase inhibitor sorafenib reduce its efficacy in hepatocellular carcinoma (HCC) treatment. Drug-resistant cancer cells frequently exhibit sphingolipid dysregulation, reducing chemotherapeutic cytotoxicity via the induction of ceramide-degrading enzymes. However, the role of ceramide in sorafenib therapy and resistance in HCC has not been clearly established. Our data reveals that ceramide-modifying enzymes, particularly glucosylceramide synthase (GCS), are upregulated during sorafenib treatment in hepatoma cells (HepG2 and Hep3B), and more importantly, in sorafenib-resistant cell lines. GCS silencing or pharmacological GCS inhibition sensitized hepatoma cells to sorafenib exposure. GCS inhibition, combined with sorafenib, triggered cytochrome c release and ATP depletion in sorafenib-treated hepatoma cells, leading to mitochondrial cell death after energetic collapse. Conversely, genetic GCS overexpression increased sorafenib resistance. Of interest, GCS inhibition improved sorafenib effectiveness in a xenograft mouse model, recovering drug sensitivity of sorafenib-resistant tumors in mice. In conclusion, our results reveal GCS induction as a mechanism of sorafenib resistance, suggesting that GCS targeting may be a novel strategy to increase sorafenib efficacy in HCC management, and point to target the mitochondria as the subcellular location where sorafenib therapy could be potentiated.
Scientific Reports | 2015
Cristina Bárcena; Milica Stefanovic; Anna Tutusaus; Guillermo A. Martínez-Nieto; Laura Martínez; Carmen García-Ruiz; Alvaro de Mingo; Juan Caballería; José C. Fernández-Checa; Montserrat Marí; Albert Morales
Hepatocellular carcinoma (HCC) frequently develops in a pro-inflammatory and pro-fibrogenic environment with hepatic stellate cells (HSCs) remodeling the extracellular matrix composition. Molecules secreted by liver tumors contributing to HSC activation and peritumoral stromal transformation remain to be fully identified. Here we show that conditioned medium from HCC cell lines, Hep3B and HepG2, induced primary mouse HSCs transdifferentiation, characterized by profibrotic properties and collagen modification, with similar results seen in the human HSC cell line LX2. Moreover, tumor growth was enhanced by coinjection of HepG2/LX2 cells in a xenograft murine model, supporting a HCC-HSC crosstalk in liver tumor progression. Protein microarray secretome analyses revealed angiogenin as the most robust and selective protein released by HCC compared to LX2 secreted molecules. In fact, recombinant angiogenin induced in vitro HSC activation requiring its nuclear translocation and rRNA transcriptional stimulation. Moreover, angiogenin antagonism by blocking antibodies or angiogenin inhibitor neomycin decreased in vitro HSC activation by conditioned media or recombinant angiogenin. Finally, neomycin administration reduced tumor growth of HepG2-LX2 cells coinjected in mice. In conclusion, angiogenin secretion by HCCs favors tumor development by inducing HSC activation and ECM remodeling. These findings indicate that targeting angiogenin signaling may be of potential relevance in HCC management.
Oncotarget | 2018
Anna Tutusaus; Milica Stefanovic; Loreto Boix; Blanca Cucarull; Aynara Zamora; Laura Blasco; Pablo García de Frutos; Maria Reig; José C. Fernández-Checa; Montserrat Marí; Anna Colell; Jordi Bruix; Albert Morales
Sorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however, their role in HCC therapy with sorafenib/regorafenib remains uncertain. BH3-mimetic ABT-263 (navitoclax) enhanced sorafenib activity, inducing cell death via a mitochondrial caspase-dependent mechanism, after BCL-xL/BCL-2 inhibition. Sorafenib-resistant hepatoma cells (HepG2R and Hep3BR) exhibited altered mRNA expression of BCL-2 and other anti-apoptotic family members, such as MCL-1, priming drug-resistant cancer cells to death by BH3-mimetics. ABT-263 restored sorafenib efficacy in sorafenib-resistant cell lines and HCC mouse models. Moreover, in mice xenografts from patient-derived BCLC9 cells, better tumor response to sorafenib was associated to higher changes in the BCL-2 mRNA pattern. HCC non-treated patients displayed altered BCL-2, MCL-1 and BCL-xL mRNA levels respect to adjacent non-tumoral biopsies and an increased BCL-2/MCL-1 ratio, predictive of navitoclax efficacy. Moreover, regorafenib administration also modified the BCL-2/MCL-1 ratio and navitoclax sensitized hepatoma cells to regorafenib by a mitochondrial caspase-dependent mechanism. In conclusion, sorafenib/regorafenib response is determined by BCL-2 proteins, while increased BCL-2/MCL-1 ratio in HCC sensitizes drug resistant-tumors against ABT-263 co-administration. Thus, changes in the BCL-2 profile, altered in HCC patients, could help to follow-up sorafenib efficacy, allowing patient selection for combined therapy with BH3-mimetics or early switch them to second line therapy.
Journal of Hepatology | 2016
Albert Morales; Anna Tutusaus; José C. Fernández-Checa; Montserrat Marí; Milica Stefanovic
Trabajo presentado en el International Liver Congress, celebrado en Barcelona, Espana, del 13 al 17 de abril de 2016
Journal of Hepatology | 2015
Anna Tutusaus; Milica Stefanovic; J.C. Fernandez-Checa; Montserrat Marí; Albert Morales
Trabajo presentado en el 50th International Liver Congress, celebrado en Viena, Austria, del 22 al 26 de abril de 2015
Journal of Hepatology | 2015
Milica Stefanovic; Anna Tutusaus; Cristina Bárcena; Guillermo A. Martínez-Nieto; Montserrat Marí; Carmen García-Ruiz; J.C. Fernandez-Checa; Albert Morales
Trabajo presentado en el 50th International Liver Congress, celebrado en Viena, Austria, del 22 al 26 de abril de 2015
Journal of Hepatology | 2014
Cristina Bárcena; Milica Stefanovic; Anna Tutusaus; Leonel Joannas; Joan Caballería; Montserrat Marí; José C. Fernández-Checa; Carla V. Rothlin; P. Garcia de Frutos; Albert Morales
Background and Aims: AXL, a receptor tyrosin kinase, and its ligand GAS6 are related to processes leading to cell differentiation and carcinogenesis. The role of GAS6/AXL signaling in hepatic stellate cell (HSC) transformation during liver disease has been insufficiently addressed. Methods: HSCs were isolated from wild-type and AXL knockout (KO) mice. HSCs and LX2 human activated HSCs were exposed to recombinant GAS6, AXL inhibitor (BGB324, BerGenBio) or siRNA silencing. p-AXL, p-AKT and HSC transformation were evaluated by western blotting and qPCR. CCl4-induced fibrosis was analyzed in wild-type and AXL KO mice. Gas6 and soluble AXL (sAXL) levels were measured by ELISA in serum from alcoholic patients with normal liver, compensated cirrhosis and decompensated cirrhosis, and in control individuals (n = 10, each group). Results: Recombinant GAS6 stimulated AXL and AKT activation, inducing phenotypic changes in primary HSCs. HSCs from AXL KO mice displayed reduced capacity to be activated in vitro, and AXL inhibition (BGB324, Bergenbio) reduced HSC activation and proliferation. Similar results were obtained in LX2 cells and after RNA silencing of AXL. Chronic CCl4 administration increased serum levels of sAXL and GAS6, while AXL deficient mice exhibited reduced liver fibrosis. More importantly, AXL inhibition (BGB324) efficiently diminished CCl4-induced liver fibrosis in wild-type mice. In parallel, GAS6 and sAXL levels in serum were increased in alcoholic liver disease (ALD) patients, inversely correlating with liver functionality. Conclusions: AXL inhibitors have clinical interest since AXL targeting is effective to treat experimental liver fibrosis. In addition, GAS6 and sAXL levels could be proposed as early prognostic markers in liver disease.
Journal of Hepatology | 2018
Anna Tutusaus; Milica Stefanovic; B. Cucarull; Montserrat Marí; Loreto Boix; Maria Reig; Jordi Bruix; Albert Morales
Journal of Hepatology | 2018
Anna Tutusaus; E.D. Gregorio; B. Cucarull; H. Cristobal; I. Graupera; G. Gausdal; A. Holmes; J. Lores; P.G. de Frutos; Montserrat Marí; Albert Morales