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Colorectal cancer cells can transfer the oncogene KRAS to distant cells, predisposing them to malignant transformation (Genometastasis Theory). This process could contribute to liver metastasis; besides, hepatic progenitor cells (HPCs) have been found to be involved in liver malignant neoplasms. The objective of this study is to determine if mouse HPCs—Oval cells (OCs)—are susceptible to incorporate Kras GAT (G12D) mutation from mouse colorectal cancer cell line CT26.WT and if OCs with the incorporated mutation behave like malignant cells. To achieve this, three lines of OCs in diferent conditions were exposed to CT26.WT cells through transwell co-culture for a week. The presence of KrasG12D and capacity to form tumors were analyzed in treated samples by droplet digital PCR and colony-forming assays, respectively. The results showed that the KrasG12D mutation was detected in hepatic culture conditions of undiferentiated OCs and these cells were capable of forming tumors in vitro. Therefore, OCs are susceptible to malignant transformation by horizontal transfer of DNA with KrasG12D mutation in an undiferentiated condition associated with the liver microenvironment. This study contributes to a new step in the understanding of the colorectal metastatic process, Tis study was supported by Conchita Rábago Foundation, Madrid, Spain by a doctoral scholarship to Rocío Olivera-Salazar, Instituto de Salud Carlos III (ISCIII), European Regional Development Fund (ERDF) (PI20/01052), Instituto de Salud Carlos III (ISCIII), and Spanish Network of Cell Terapy (TerCel) (RD16/0011/0013).

El presente trabajo pretende ser una aproximación al estudio de la política exterior de México en el período comprendido entre 1934 y 1940, es decir, bajo el mandato del General Lázaro Cárdenas. La elección del sexenio cardenista no es casual. Durante los últimos años del sistema internacional de entreguerras en México se decide el destino de miles de personas que tuvieron que huir de su país ante la persecución del fascismo triunfante tras la Guerra Civil Española. Ahora, con el paso del tiempo, es sabido que muchos de esos exiliados pudieron salvar sus vidas gracias a la decisión del General Cárdenas y al apoyo del pueblo mexicano. Pero la ayuda de México a la República Española fue más allá del asilo diplomático a los exiliados. México se convirtió en el defensor del gobierno republicano español en todos los foros internacionales donde tuvo oportunidad de hacerlo. Su lealtad a la República Española fue inquebrantable hasta el punto de ser el único país del mundo que no reconoció jurídicamente al régimen del general golpista Francisco Franco.

16 p.-6 fig.-1 graph. abst., Adult hepatic progenitor cells (HPCs)/oval cells are bipotential progenitors that participate in liver repair responses upon chronic injury. Recent findings highlight HPCs plasticity and importance of the HPCs niche signals to determine their fate during the regenerative process, favoring either fibrogenesis or damage resolution. Transforming Growth Factor-β (TGF-β) and Hepatocyte Growth Factor (HGF) are among the key signals involved in liver regeneration and as component of HPCs niche regulate HPCs biology. Here, we characterize the TGF-β-triggered epithelial-mesenchymal transition (EMT) response in oval cells, its effects on cell fate in vivo, and the regulatory effect of the HGF/c-Met signaling. Our data show that chronic treatment with TGF-β triggers a partial EMT in oval cells, based on co-expression of epithelial and mesenchymal markers. The phenotypic and functional profiling indicate that TGF-β-induced EMT is not associated with stemness but rather represents a step forward along hepatic lineage. This phenotypic transition confers advantageous traits to HPCs including survival, migratory/invasive and metabolic benefit, overall enhancing the regenerative potential of oval cells upon transplantation into a carbon tetrachloride-damaged liver. We further uncover a key contribution of the HGF/c-Met pathway to modulate the TGF-β-mediated EMT response. It allows oval cells expansion after EMT by controlling oxidative stress and apoptosis, likely via Twist regulation, and it counterbalances EMT by maintaining epithelial properties. Our work provides evidence that a coordinated and balanced action of TGF-β and HGF are critical for achievement of the optimal regenerative potential of HPCs, opening new therapeutic perspectives. SIGNIFICANCE STATEMENT: The findings from this study support that a balanced action of TGF-ß and HGF could determine liver progenitors fate and the outcome of liver regeneration, and open possibilities for targeted therapies oriented at improving the regenerative capacity of these cells in chronic liver diseases., This work was supported by a Marie Curie Action FP7-2012(Grant #PITN-GA-2012-316549; IT-LIVER); Ministry of Science,Innovation and Universities, Spain (Grant #SAF2015-69145-R) and General Direction of Universities and Research of theAutonomous Community of Madrid, Spain (Grant #S2010/BMD-2402, MITOLAB consortium). LA was recipient of a pre-doctoral contract from UCM. MG-A, AMP and NL were recipients from research-training contracts from Grant #S2010/BMD-2402 and SAF2006-12025 (Ministry of Education and Sci-ence) and SAF2015-69145-R, respectively.

Resumen del póster presentado al 42nd Congress of the Spanish Society of Biochemistry and Molecular Biology (SEBBM), celebrado en Madrid del 16 al 19 de julio de 2019., Oval cells are progenitor cells with an emerging role in liver regenerative responses. However, their susceptibility to lipotoxicity in obesity-associated insulin resistance is unknown. Inhibition of protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin signaling, is a pharmacological strategy against insulin resistance/obesity. Ours aims were to identify whether oval cells are insulin target cells and to analyze the impact of PTP1B deficiency in their susceptibility to lipotoxicity in the context of obesity-associated non-alcoholic fatty liver disease (NAFLD). For lipotoxicity studies, oval cells were treated with palmitic acid (PA) for different time-periods, after which oxidative/endoplasmic reticulum (ER) stress responses and autophagy/apoptosis markers were analyzed. A lipidomic study was conducted to characterize the intracellular lipid species upon PA stimulation. Oval cells responded to insulin by inducing insulin receptor tyrosine phosphorylation, this effect being higher in the absence of PTP1B. Treatment with PA induced apoptotic cell death in PTP1B+/+ oval cells in parallel with a blockade of the autophagy flux. Cell death was not found in PTP1B-/- cells that accumulated lipid droplets and increased perilipin2 levels upon PA treatment. Cell death in PA-treated PTP1B+/+ oval cells was prevented by cotreatment with sulforaphane, a Nrf2 activator. Also, PTP1B-/- oval cells showed higher basal levels of HO-1 and catalase, suggesting constitutive anti-oxidant defense. An early activation of ER stress was found in both genotypes but this response was enhanced in PTP1B-/- cells in both basal and upon PA treatment. Lipidomics revealed that PTP1B-/- oval cells accumulated triglyceride species and cholesterol esters in response to PA. By contrast, PTP1B+/+ oval cells showed higher diacylglycerides, more toxic lipid species. In conclusion, we have revealed that oval cells are insulin target cells susceptible to lipotoxicity, an effect mediated at least in part by the induction of oxidative stress. PTP1B deficiency protects against lipotoxic cell death by mechanisms including enhancement of anti-oxidant defences and capacity to accumulate TG containing lipid droplets, suggesting a potential benefit in cellular regenerative therapies against NAFLD.