The bitter side of epigenetics: variability and resistance to chemotherapy

One of the major obstacles to the development of effective new cancer treatments and the main factor for the increasing number of clinical trial failures appears to be the paucity of accurate, reproducible and robust drug resistance testing methods. Most research assessing the resistance of cancers to chemotherapy has concentrated on genetic-based molecular mechanisms, while the role of epigenetics in drug resistance has been generally overlooked. This is rather surprising given that an increasing body of evidence pointing to the fact that epigenetic mechanism alterations appear to play a pivotal role in cancer initiation, progression and development of chemoresistance. This resulted in a series of clinical trials involving epi-drug as single treatment or combined with cancer conventional drugs. In this review, we provided the main mechanisms by which the epigenetic regulators control the resistance to cancer drugs

With their backs to the Sea. Challenges for an Integrated Management of the Coastal and Maritime Archaeological Heritage of Uruguay

Uruguay faces a new challenge in managing the country’s coastal and maritime archaeological heritage. Diversification and intensification of activities on the coast and in the marine environment put at risk a cultural heritage that has very weak legal protection and lacks strong public management policies. This work collects information on the current situation of the country’s coastal and maritime archaeological heritage, its legal-administrative status and the new scenarios of economic development in the coastal area, continental shelf and Offshore. It reviews the main impacts and threats that these socio-economic activities cover for this heritage. Concludes by emphasizing the necessary articulation of cultural heritage resource management within the framework of Integrated Coastal Management and Marine Spatial Planning, which enable sustainable development of the coastal-maritime territory for the conservation of its most precious resources, including historical-cultural components.Uruguay enfrenta un nuevo desafío en la gestión del patrimonio arqueológico costero y marítimo del país. La diversificación e incremento de actividades en la costa y en el medio marino ponen en riesgo un patrimonio cultural con una muy débil protección jurídica, que carece de fuertes políticas públicas para su manejo y gestión. Se recopila información sobre la situación actual del patrimonio arqueológico costero y marítimo, su condición jurídico-administrativa y los nuevos escenarios de desarrollo del sector económico en la zona costera, plataforma continental y offshore. Se revisan los principales impactos y amenazas que dichas actividades socio económicas revisten para el patrimonio. Se recomienda la urgente articulación de la gestión de estos recursos en el marco del Manejo Costero Integrado y la Planificación Espacial Marina, que posibiliten un desarrollo sustentable del territorio costero-marítimo del país y la conservación de sus recursos más preciados, incluyendo sus componentes histórico-culturales

De Espaldas al Mar. Desafíos para un Manejo Integrado del Patrimonio Arqueológico Costero y Marítimo del Uruguay

Uruguay faces a new challenge in managing the country’s coastal and maritime archaeological heritage. Diversification and intensification of activities on the coast and in the marine environment put at risk a cultural heritage that has very weak legal protection and lacks strong public management policies. This work collects information on the current situation of the country’s coastal and maritime archaeological heritage, its legal-administrative status and the new scenarios of economic development in the coastal area, continental shelf and Offshore. It reviews the main impacts and threats that these socio-economic activities cover for this heritage. Concludes by emphasizing the necessary articulation of cultural heritage resource management within the framework of Integrated CoastalManagement and Marine Spatial Planning, which enableUruguay enfrenta un nuevo desafío en la gestión del patrimonio arqueológico costero y marítimo del país. La diversificación e incremento de actividades en la costa y en el medio marino ponen en riesgo un patrimonio cultural con una muy débil protección jurídica, que carece de fuertes políticas públicas para su manejo y gestión. Se recopila información sobre la situación actual del patrimonio arqueológico costero y marítimo, su condición jurídico-administrativa y los nuevos escenarios de desarrollo del sector económico en la zona costera, plataforma continental y offshore. Se revisan los principales impactos y amenazas que dichas actividades socio económicas revisten para el patrimonio. Se recomienda la urgente articulación de la gestión de estos recursos en el marco del Manejo Costero Integrado y la Planificación Espacial Marina, que posibiliten un desarrollo sustentable del territorio costero-marítimo del país y la conservación de sus recursos más preciados, incluyendo sus componentes histórico-culturales

Anàlisi de procediments per a la creació i gestió del coneixement mitjançant comunitats de pràctica a l'administració pública

En la societat actual el coneixement s'està erigint com un bé de gran valor estratègic i es busquen formes de crear, gestionar, controlar i posseir aquest coneixement. En aquest sentit, en aquest estudi ens interessen els actors i processos vinculats a la CGC (Del Moral et al., 2007; Drucker, 2003; Holsapple i Wu, 2008) i, com no, la pròpia gestió del coneixement (Basu y Sengupta, 2007; dePaula y Fischer, 2005; Milton, 2005; Stankosky, 2005; Weber, 2007).El propòsit de la recerca que es presenta va ser analitzar procediments de creació i gestió del coneixement en comunitats de pràctica generades en l'àmbit de l'administració púbica, i amb ús intensiu de tecnologia, amb l'objectiu de delimitar els factors d'èxit de les comunitats analitzades per tal de crear un mapa de bones pràctiques, tot concretant protocols d'intervenció i estàndards de qualitat. El mètode utilitzat per a la re cerca ha estat l'estudi de cas. Concretament, s'utilitzà el multicas, en el qual s'ha generat una innovació organitzativa (processo~de CGC) adoptada per algunes organitzacions o comunitats (casos individuals), però, en realitat, el que ens interessa és l'estudi global de totes elles. Com indica Yin (2009), aquest tipus d'estudi multicas resulta més robust i consistent que l'estudi de casos individuals.Els resultats de la recerca han permès la identificació d'indicadors, l'establiment d'estàndards, la determinació de bones pràctiques i la creació d'una Guia d'autoavaluació per a la millora de les comunitats de pràctica existents o que es creïn a l'àmbit de l'administració públic

Métodos de valoración de la interfase hueso-implante: análisis de la producción científica (1997-2007

Objetivos: Realizar un análisis estadístico descriptivo y bibliométrico de las fuentes bibliográficas periódicas relacionadas con los métodos de valoración de la interfase hueso-implante publicadas entre los años 1997 y 2007. Diseño del estudio: Se obtuvo una muestra de 224 artículos como resultado de la consulta de diez repertorios, nacionales e internacionales, accesibles desde los recursos electrónicos de la biblioteca de la Universidad de Sevilla. El análisis de los datos obtenidos se llevó a cabo en función de la base de datos, en la que se encontró, el año de su publicación, país de origen e idioma. Se comprobó la validez de las leyes de Price, Lotka y Bradford sobre esta muestra. Resultados: Señalamos la importancia de EE. UU. como principal país productor de artículos sobre métodos de valoración de la interfase hueso-implante, aunque si agrupamos los países por zonas geográficas, Europa occidental es la de mayor producción. Conclusiones: Las leyes de Lotka y Bradford sí se cumplen en nuestra muestra (coeficiente de correlación de 1 y 0,99), mientras que la ley de Price no (coeficiente de correlación, 0,20), lo que se traduce en un estancamiento de la producción científica en esta área en el periodo estudiado

Selective histone methyltransferase G9a inhibition reduces metastatic development of Ewing sarcoma through the epigenetic regulation of NEU1

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor with high susceptibility to metastasize. The underlying molecular mechanisms leading to EWS metastases remain poorly understood. Epigenetic changes have been implicated in EWS tumor growth and progression. Linking epigenetics and metastases may provide insight into novel molecular targets in EWS and improve its treatment. Here, we evaluated the effects of a selective G9a histone methyltransferase inhibitor (BIX01294) on EWS metastatic process. Our results showed that overexpression of G9a in tumors from EWS patients correlates with poor prognosis. Moreover, we observe a significantly higher expression of G9a in metastatic EWS tumor as compared to either primary or recurrent tumor. Using functional assays, we demonstrate that pharmacological G9a inhibition using BIX01294 disrupts several metastatic steps in vitro, such as migration, invasion, adhesion, colony formation and vasculogenic mimicry. Moreover, BIX01294 reduces tumor growth and metastases in two spontaneous metastases mouse models. We further identified the sialidase NEU1 as a direct target and effector of G9a in the metastatic process in EWS. NEU1 overexpression impairs migration, invasion and clonogenic capacity of EWS cell lines. Overall, G9a inhibition impairs metastases in vitro and in vivo through the overexpression of NEU1. G9a has strong potential as a prognostic marker and may be a promising therapeutic target for EWS patients

Multidrug resistance transporter profile reveals MDR3 as a marker for stratification of blastemal Wilms tumour patients

Wilms tumour (WT) is the most common renal tumour in children. Most WT patients respond to chemotherapy, but subsets of tumours develop resistance to chemotherapeutic agents, which is a major obstacle in their successful treatment. Multidrug resistance transporters play a crucial role in the development of resistance in cancer due to the efflux of anticancer agents out of cells. The aim of this study was to explore several human multidrug resistance transporters in 46 WT and 40 nonneoplastic control tissues (normal kidney) from patients selected after chemotherapy treatment SIOP 93–01, SIOP 2001. Our data showed that the majority of the studied multidrug resistance transporters were downregulated or unchanged between tumours and control tissues. However, BCRP1, MDR3 and MRP1 were upregulated in tumours versus control tissues. MDR3 and MRP1 overexpression correlated with highrisk tumours (SIOP classification) (p = 0.0022 and p < 0.0001, respectively) and the time of disease-free survival was significantly shorter in patients with high transcript levels of MDR3 (p = 0.0359). MDR3 and MRP1 play a role in drug resistance in WT treatment, probably by alteration of an unspecific drug excretion system. Besides, within the blastemal subtype, we observed patients with low MDR3 expression were significantly associated with a better outcome than patients with high MDR3 expression. We could define two types of blastemal WT associated with different disease outcomes, enabling the stratification of blastemal WT patients based on the expression levels of the multidrug resistance transporter MDR3.Ministerio de Economía y Competitividad PI1401466, RD06/0020/0059, PI1100018, CD06/00001Red Tematica de Investigacion Cooperativa en Cancer RD12/0036/0017Unión Europea FP7-HEALTH- 2011-two-stage, Project ID 278742 EUROSARCInstituto de Salud Carlos III FIS PI13/0228

VE-Cadherin modulates ß-catenin/TCF-4 to enhance Vasculogenic Mimicry

Vasculogenic Mimicry (VM) refers to the capacity to form a blood network from aggressive cancer cells in an independent way of endothelial cells, to provide nutrients and oxygen leading to enhanced microenvironment complexity and treatment failure. In a previous study, we demonstrated that VE-Cadherin and its phosphorylation at Y658 modulated kaiso-dependent gene expression (CCND1 and Wnt 11) through a pathway involving Focal Adhesion kinase (FAK). In the present research, using a proteomic approach, we have found that ß-catenin/TCF-4 is associated with nuclear VE-cadherin and enhances the capacity of malignant melanoma cells to undergo VM in cooperation with VE-Cadherin; in addition, preventing the phosphorylation of Y658 of VEcadherin upon FAK disabling resulted in VE-Cadherin/ß-catenin complex dissociation, increased ß-catenin degradation while reducing TCF-4-dependent genes transcription (C-Myc and Twist-1). Uveal melanoma cells knockout for VE-Cadherin loses ß-catenin expression while the rescue of VE-Cadherin (but not of the phosphorylation defective VE-Cadherin Y658F mutant) permits stabilization of ß-catenin and tumor growth reduction in vivo experiments. In vivo, the concomitant treatment with the FAK inhibitor PF-271 and the anti-angiogenic agent bevacizumab leads to a strong reduction in tumor growth concerning the single treatment. In conclusion, the anomalous expression of VE-Cadherin in metastatic melanoma cells (from both uveal and cutaneous origins), together with its permanent phosphorylation at Y658, favors the induction of the aggressive VM phenotype through the cooperation of ß-catenin with VE-Cadherin and by enhancing TCF-4 genes-dependent transcription.This work was supported by grants from the Spanish Ministry of Economy and Competitiveness SAF2015-70520-R, the Spanish Ministry of Science and Technology RTI2018-098968-B-I00, CIBERONC ISCIII CB16/12/00421 and Junta de Andalucía, a project of Excellence from Junta de Andalucía P10-CTS-0662, P12-CTS-383 to FJO. Fundación Domingo Martínez to FJO. Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (PAIDI 2020, POSTDOC_21_00865) to DD-B. Fundación Getthi ONC18PE01/2022 to DAE, AT

Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions

[Background] The adaptation to hypoxia is mainly controlled by the HIF transcription factors. Increased expression/activity of HIF-1α correlates with poor prognosis in cancer patients. PARP-1 inhibitors are used in the clinic to treat BRCAness breast/ovarian cancer and have been shown to regulate the hypoxic response; therefore, their use could be expanded.[Methods] In this work by integrating molecular/cell biology approaches, genome-wide ChIP-seq, and patient samples, we elucidate the extent to which PARP-1 exerts control over HIF-1-regulated genes.[Results] In human melanoma, PARP-1 and HIF-1α expression are strongly associated. In response to a hypoxic challenge poly(ADP-ribose) (PAR) is synthesized, HIF-1α is post-transcriptionally modified (PTM) and stabilized by PARylation at specific K/R residues located at its C-terminus. Using an unbiased ChIP-seq approach we demonstrate that PARP-1 dictates hypoxia-dependent HIF-recruitment to chromatin in a range of HIF-regulated genes while analysis of HIF-binding motifs (RCGTG) reveals a restriction on the recognition of hypoxia responsive elements in the absence of PARP-1. Consequently, the cells are poorly adapted to hypoxia, showing a reduced fitness during hypoxic induction.[Conclusions] These data characterize the fine-tuning regulation by PARP-1/PARylation of HIF activation and suggest that PARP inhibitors might have therapeutic potential against cancer types displaying HIF-1α over-activation.This work was supported by Junta de Andalucía, project of Excellence from Junta de Andalucía P10-CTS-0662, P12-CTS-383 to FJO, Spanish Ministry of Economy and Competitiveness SAF2012-40011-C02-01, SAF2015-70520- R, RTI2018-098968-B-I00, RTICC RD12/0036/0026 and CIBER Cáncer ISCIII CB16/12/00421 to FJO. EB1s lab is supported by the Basque Department of Industry, Tourism and Trade (Etortek) and the MINECO (CB16/12/00421) grants. Fundación Domingo Martínez (call 2019).Peer reviewe

E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor

KIT/PDGFRA oncogenic tyrosine kinase signaling is the central oncogenic event in most gastrointestinal stromal tumors (GIST), which are human malignant mesenchymal neoplasms that often feature myogenic differentiation. Although targeted inhibition of KIT/PDGFRA provides substantial clinical benefit, GIST cells adapt to KIT/PDGFRA driver suppression and eventually develop resistance. The specific molecular events leading to adaptive resistance in GIST remain unclear. By using clinically representative in vitro and in vivo GIST models and GIST patients’ samples, we found that the E3 ubiquitin ligase Atrogin-1 (FBXO32)—the main effector of muscular atrophy in cachexia—resulted in the most critical gene derepressed in response to KIT inhibition, regardless the type of KIT primary or secondary mutation. Atrogin-1 in GISTs is transcriptionally controlled by the KIT-FOXO3a axis, thus indicating overlap with Atrogin-1 regulation mechanisms in nonneoplastic muscle cells. Further, Atrogin-1 overexpression was a GIST-cell-specific pro-survival mechanism that enabled the adaptation to KIT-targeted inhibition by apoptosis evasion through cell quiescence. Buttressed on these findings, we established in vitro and in vivo the preclinical proof-of-concept for co-targeting KIT and the ubiquitin pathway to maximize the therapeutic response to first-line imatinib treatment.This project was funded by the 2014 SARC International Career Development Award (SARC Sarcoma Spore 1U54CA168512–01), Fundación Mari Paz Jiménez Casado, FERO Foundation, Spanish Society of Medical Oncology (SEOM), PERIS SLT006/17/221, ISCIII PI16/01371 and PI19/01271, all to C.S. ISCIII FI20/00275 (to DG-P), and a Ph.D. fellowship from the National Secretary for Higher Education, Science, Technology and Innovation of Ecuador (SENESCYT) (to DFP-J). AE-C is funded by ISCIII PT17/0009/0019 and co-funded by FEDER