Person: Bragado Domingo, Paloma
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First Name
Paloma
Last Name
Bragado Domingo
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Bioquímica y Biología Molecular
Area
Bioquímica y Biología Molecular
Identifiers
3 results
Search Results
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Item New and Old Key Players in Liver Cancer(International Journal of Molecular Sciences, 2023) Cuesta Martínez, Ángel; Palao, Nerea; Bragado Domingo, Paloma; Gutiérrez Uzquiza, Álvaro; Herrera González, Blanca María; Sánchez Muñoz, Aranzazu; Porras Gallo, María AlmudenaLiver cancer represents a major health problem worldwide with growing incidence and high mortality, hepatocellular carcinoma (HCC) being the most frequent. Hepatocytes are likely the cellular origin of most HCCs through the accumulation of genetic alterations, although hepatic progenitor cells (HPCs) might also be candidates in specific cases, as discussed here. HCC usually develops in a context of chronic inflammation, fibrosis, and cirrhosis, although the role of fibrosis is controversial. The interplay between hepatocytes, immune cells and hepatic stellate cells is a key issue. This review summarizes critical aspects of the liver tumor microenvironment paying special attention to platelets as new key players, which exert both pro- and anti-tumor effects, determined by specific contexts and a tight regulation of platelet signaling. Additionally, the relevance of specific signaling pathways, mainly HGF/MET, EGFR and TGF-β is discussed. HGF and TGF-β are produced by different liver cells and platelets and regulate not only tumor cell fate but also HPCs, inflammation and fibrosis, these being key players in these processes. The role of C3G/RAPGEF1, required for the proper function of HGF/MET signaling in HCC and HPCs, is highlighted, due to its ability to promote HCC growth and, regulate HPC fate and platelet-mediated actions on liver cancer.Item New and Old Key Players in Liver Cancer(International Journal of Molecular Sciences, 2023) Cuesta Martínez, Ángel; Palao, Nerea; Bragado Domingo, Paloma; Gutiérrez Uzquiza, Álvaro; Herrera González, Blanca María; Sánchez Muñoz, Aranzazu; Porras Gallo, María Almudena; Arechederra, Maria; Tarantino, Giovanni; Berasain, CarmenLiver cancer represents a major health problem worldwide with growing incidence and high mortality, hepatocellular carcinoma (HCC) being the most frequent. Hepatocytes are likely the cellular origin of most HCCs through the accumulation of genetic alterations, although hepatic progenitor cells (HPCs) might also be candidates in specific cases, as discussed here. HCC usually develops in a context of chronic inflammation, fibrosis, and cirrhosis, although the role of fibrosis is controversial. The interplay between hepatocytes, immune cells and hepatic stellate cells is a key issue. This review summarizes critical aspects of the liver tumor microenvironment paying special attention to platelets as new key players, which exert both pro- and anti-tumor effects, determined by specific contexts and a tight regulation of platelet signaling. Additionally, the relevance of specific signaling pathways, mainly HGF/MET, EGFR and TGF-β is discussed. HGF and TGF-β are produced by different liver cells and platelets and regulate not only tumor cell fate but also HPCs, inflammation and fibrosis, these being key players in these processes. The role of C3G/RAPGEF1, required for the proper function of HGF/MET signaling in HCC and HPCs, is highlighted, due to its ability to promote HCC growth and, regulate HPC fate and platelet-mediated actions on liver cancer.Item Lack of EGFR catalytic activity in hepatocytes improves liver regeneration following DDC‐induced cholestatic injury by promoting a pro‐restorative inflammatory response(Journal of Pathology, 2022) Lazcanoiturburu, Nerea; García‐Sáez, Juan; González‐Corralejo, Carlos; Roncero Romero, Cesáreo; Sanz Ortega, Julián; Martín‐Rodríguez, Carlos; Valdecantos, M Pilar; Martínez‐Palacián, Adoración; Almale Del Barrio, Laura; Bragado Domingo, Paloma; Calero‐Pérez, Silvia; Fernández, Almudena; García‐Bravo, María; Guerra, Carmen; Montoliu, Lluis; Segovia, José Carlos; Martínez Valverde, Ángela María; Fabregat Romero, María Isabel; Herrera González, Blanca María; Sánchez Muñoz, AranzazuDespite the well‐known hepatoprotective role of the epidermal growth factor receptor (EGFR) pathway upon acute damage, its specific actions during chronic liver disease, particularly cholestatic injury, remain ambiguous and unresolved. Here, we analyzed the consequences of inactivating EGFR signaling in the liver on the regenerative response following cholestatic injury. For that, transgenic mice overexpressing a dominant negative mutant human EGFR lacking tyrosine kinase activity (ΔEGFR) in albumin‐positive cells were submitted to liver damage induced by 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC), an experimental model resembling human primary sclerosing cholangitis. Our results show an early activation of EGFR after 1–2 days of a DDC‐supplemented diet, followed by a signaling switch‐off. Furthermore, ΔEGFR mice showed less liver damage and a more efficient regeneration following DDC injury. Analysis of the mechanisms driving this effect revealed an enhanced activation of mitogenic/survival signals, AKT and ERK1/2‐MAPKs, and changes in cell turnover consistent with a quicker resolution of damage in response to DDC. These changes were concomitant with profound differences in the profile of intrahepatic immune cells, consisting of a shift in the M1/M2 balance towards M2 polarity, and the Cd4/Cd8 ratio in favor of Cd4 lymphocytes, overall supporting an immune cell switch into a pro‐restorative phenotype. Interestingly, ΔEGFR livers also displayed an amplified ductular reaction, with increased expression of EPCAM and an increased number of CK19‐positive ductular structures in portal areas, demonstrating an overexpansion of ductular progenitor cells. In summary, our work supports the notion that hepatocyte‐specific EGFR activity acts as a key player in the crosstalk between parenchymal and non‐parenchymal hepatic cells, promoting the pro‐inflammatory response activated during cholestatic injury and therefore contributing to the pathogenesis of cholestatic liver disease. © 2022 The Pathological Society of Great Britain and Ireland.