Artículos (Biología Celular)

URI permanente para esta colecciónhttps://hdl.handle.net/11441/10814

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Enhancing human islet xenotransplant survival and function in diabetic immunocompetent mice through LRH-1/NR5A2 pharmacological activation
(Frontiers Media S.A., 2024-09-27) Cobo-Vuilleumier, N.; Lorenzo, P.I.; Vazquez, E.M.; López Noriega, Livia; Nano, R.; Piemonti, L.; Martín, F.; Gauthier, B.R.; Universidad de Sevilla. Departamento de Biología Celular; Junta de Andalucía; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación (AEI); Sociedad Española de Diabetes (SED); The Juvenile Diabetes Research Foundation (JDRF)
The intricate etiology of type 1 diabetes mellitus (T1D), characterized by harmful interactions between the immune system and insulin-producing beta cells, has hindered the development of effective therapies including human islet transplantation, which requires strong immunosuppressants that impair beta cell survival and function. As such alternative immunomodulating therapies are required for successful transplantation. The discovery that pharmacological activation of the nuclear receptor LRH-1/NR5A2 can reverse hyperglycemia in mouse models of T1D by altering, and not suppressing the autoimmune attack, prompted us to investigate whether LRH-1/NR5A2 activation could improve human islet function/survival after xenotransplantation in immunocompetent mice. Human islets were transplanted under the kidney capsule of streptozotocin (STZ)-induced diabetic mice, and treatment with BL001 (LRH-1/NR5A2 agonist) or vehicle was administered one week post-transplant. Our study, encompassing 3 independent experiments with 3 different islet donors, revealed that mice treated for 8 weeks with BL001 exhibited lower blood glucose levels correlating with improved mouse survival rates as compared to vehicle-treated controls. Human C-peptide was detectable in BL001-treated mice at both 4 and 8 weeks indicating functional islet beta cells. Accordingly, in mice treated with BL001 for 8 weeks, the beta cell mass was preserved, while a significant decrease in alpha cells was observed compared to mice treated with BL001 for only 4 weeks. In contrast, vehicle-treated mice exhibited a reduction in insulin-expressing cells at 8 weeks compared to those at 4 weeks. These results suggest that BL001 significantly enhances the survival, engraftment, and functionality of human islets in a STZ-induced diabetic mouse model.
Neural crest derived progenitor cells contribute to tumor stroma and aggressiveness in stage 4/M neuroblastoma
(Impact Journals, 2017-09-21) Linares Clemente, Pedro; Aguilar Morante, Diana; Rodríguez Prieto, Ismael; Ramírez, Gema; Torres, Carmen de; Santamaría, Vicente; Pascual-Vaca, Diego; Colmenero-Repiso, Ana; Vega Moreno, Francisco Manuel; Pardal Redondo, Ricardo; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Asociacion Espanola contra el Cancer (AECC); European Research Council (ERC Starting Grant (CBSCs)); FEDER; Spanish Ministry of Economy and Competitiviness SAF; Universidad de Sevilla. CTS-007: Fisiopatología de células madre neurales
Pediatric tumors arise upon oncogenic transformation of stem/progenitor cells during embryonic development. Given this scenario, the existence of non-tumorigenic stem cells included within the aberrant tumoral niche, with a potential role in tumor biology, is an intriguing and unstudied possibility. Here, we describe the presence and function of non-tumorigenic neural crest-derived progenitor cells in aggressive neuroblastoma (NB) tumors. These cells differentiate into neural crest typical mesectodermal derivatives, giving rise to tumor stroma and promoting proliferation and tumor aggressiveness. Furthermore, an analysis of gene expression profiles in stage 4/M NB revealed a neural crest stem cell (NCSC) gene signature that was associated to stromal phenotype and high probability of relapse. Thus, this NCSC gene expression signature could be used in prognosis to improve stratification of stage 4/M NB tumors. Our results might facilitate the design of new therapies by targeting NCSCs and their contribution to tumor stroma.
Con el agua: ¡mójate! Un proyecto de innovación docente y alfabetización científica
(Universidad Andina Simón Bolívar, 2019-04-09) Morón Monge, Hortensia; Daza Navarro, María Paula; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Didáctica de las Ciencias Experimentales y Sociales
Se presentan los resultados de un Proyecto de Alfabetización Científica llevado a cabo por un grupo de profesoras de la Facultad de Ciencias de la Educación, de la Universidad de Sevilla (España). El objetivo de dicho proyecto es mejorar los conocimientos sobre ciencia de los estudiantes de los Grados de Infantil y Primaria, usando la temática del agua y su problemática . La innovación docente posiciona al alumnado en un lugar protagonista del proceso enseñanza-aprendizaje, donde no solo aprenden ciencias mediante el método científico sino que además toman el rol activo de divulgadores científicos desarrollando así sus competencias como docente.
RNF212B E3 ligase is essential for crossover designation and maturation during male and female meiosis in the mouse
(National Academy of Sciences, 2024-06-12) Condezo, Yazmine B.; Sáinz Urruela, Raquel; Gómez-H , Laura; Salas Lloret, Daniel; Felipe Medina, Natalia; Bradley, Rachel; González Prieto, Román; Llano, Elena; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Castilla-León
Meiosis, a reductional cell division, relies on precise initiation, maturation, and resolution of crossovers (COs) during prophase I to ensure the accurate segregation of homologous chromosomes during metaphase I. This process is regulated by the interplay of RING-E3 ligases such as RNF212 and HEI10 in mammals. In this study, we functionally characterized a recently identified RING-E3 ligase, RNF212B. RNF212B colocalizes and interacts with RNF212, forming foci along chromosomes from zygonema onward in a synapsis-dependent and DSB-independent manner. These consolidate into larger foci at maturing COs, colocalizing with HEI10, CNTD1, and MLH1 by late pachynema. Genetically, RNF212B foci formation depends on Rnf212 but not on Msh4, Hei10, and Cntd1, while the unloading of RNF212B at the end of pachynema is dependent on Hei10 and Cntd1. Mice lacking RNF212B, or expressing an inactive RNF212B protein, exhibit modest synapsis defects, a reduction in the localization of pro-CO factors (MSH4, TEX11, RPA, MZIP2) and absence of late CO-intermediates (MLH1). This loss of most COs by diakinesis results in mostly univalent chromosomes. Double mutants for Rnf212b and Rnf212 exhibit an identical phenotype to that of Rnf212b single mutants, while double heterozygous demonstrate a dosage-dependent reduction in CO number, indicating a functional interplay between paralogs. SUMOylome analysis of testes from Rnf212b mutants and pull-down analysis of Sumo-and Ubiquitin-tagged HeLa cells, suggest that RNF212B is an E3-ligase with Ubiquitin activity, serving as a crucial factor for CO maturation. Thus, RNF212 and RNF212B play vital, yet overlapping roles, in ensuring CO homeostasis through their distinct E3 ligase activities.
Dynamic modes of Notch transcription hubs conferring memory and stochastic activation revealed by live imaging the co-activator Mastermind
(eLife Sciences Publications Ltd., 2024-05-10) De Haro Arbona, F. Javier; Roussos, Charalambos; Baloul, Sarah; Townson, Jonathan; Gómez Lamarca, Mª Jesús; Bray, Sarah; Universidad de Sevilla. Departamento de Biología Celular
Developmental programming involves the accurate conversion of signalling levels and dynamics to transcriptional outputs. The transcriptional relay in the Notch pathway relies on nuclear complexes containing the co-activator Mastermind (Mam). By tracking these complexes in real time, we reveal that they promote the formation of a dynamic transcription hub in Notch ON nuclei which concentrates key factors including the Mediator CDK module. The composition of the hub is labile and persists after Notch withdrawal conferring a memory that enables rapid reformation. Surprisingly, only a third of Notch ON hubs progress to a state with nascent transcription, which correlates with polymerase II and core Mediator recruitment. This probability is increased by a second signal. The discovery that target-gene transcription is probabilistic has far-reaching implications because it implies that stochastic differences in Notch pathway output can arise downstream of receptor activation.
Real-life effectiveness of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients previously treated with sofosbuvir/velpatasvir or glecaprevir/pibrentasvir
(Wiley, 2024-05-02) Ruiz Cobo, Juan Carlos; Llaneras, Jordi; Forns, Xavier; Gallego Moya, Adolfo; Conde Amiel, Isabel; Arencibia, Ana; Rodríguez Seguel, Elisa del Pilar; Buti, María; Universidad de Sevilla. Departamento de Biología Celular
Background Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is the recommended rescue therapy for patients with chronic hepatitis C infection who fail direct-acting antivirals (DAAs). Data are limited on the effectiveness of this treatment after the current first-line therapies. Our aim was to analyse the effectiveness and safety of SOF/VEL/VOX among patients failing sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB). Methods Retrospective multicentre study (26 Spanish hospitals), including chronic hepatitis C patients unsuccessfully treated with SOF/VEL or GLE/PIB, and retreated with SOF/VEL/VOX ± ribavirin for 12 weeks between December 2017 and December 2022. Results In total, 142 patients included: 100 (70.4%) had failed SOF/VEL and 42 (29.6%) GLE/PIB. Patients were mainly men (84.5%), White (93.9%), with hepatitis C virus genotype (GT) 3 (49.6%) and 47.2% had liver cirrhosis. Sustained virological response (SVR) was evaluated in 132 patients who completed SOF/VEL/VOX and were followed 12 weeks after end of treatment; 117 (88.6%) achieved SVR. There were no significant differences in SVR rates according to initial DAA treatment (SOF/VEL 87.9% vs. GLE/PIB 90.2%, p = 0.8), cirrhosis (no cirrhosis 90% vs. cirrhosis 87.1%, p = 0.6) or GT3 infection (non-GT3 91.9% vs. GT3 85.5%, p = 0.3). However, when considering the concurrent presence of SOF/VEL treatment, cirrhosis and GT3 infection, SVR rates dropped to 82.8%. Ribavirin was added in 8 (6%) patients, all achieved SVR. Conclusion SOF/VEL/VOX is an effective rescue therapy for failures to SOF/VEL or GLE/PIB, with an SVR of 88.6%. Factors previously linked to lower SVR rates, such as GT3 infection, cirrhosis and first-line therapy with SOF/VEL were not associated with lower SVRs.
Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality
(Nature, 2024-07-24) Mora Romero, Bella; Capelo Carrasco, Nicolás; Pérez Moreno, Juan José; Álvarez Vergara, María Isabel; Trujillo Estrada, Laura Isabel; Romero Molina, Carmen; Martínez Márquez, Emilio; Morano Catalan, Noelia; Vizuete Chacón, María Luisa; López Barneo, José; Nieto González, José Luis; García-Junco Clemente, Pablo; Vitorica Ferrández, Francisco Javier; Gutiérrez, Antonia; Macías, David; Rosales Nieves, Alicia E.; Pascual Bravo, Alberto; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía
Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs.
Changes in the expression of inflammatory genes induced by chronic exercise in the adipose tissue: Differences by sex
(MDPI, 2024) Sanchis, Paula; Ezequiel Rodriguez, Aida; Sánchez Oliver, Antonio Jesús; Suarez Carmona, Walter; Lopez Martín, Sergio; García Muriana, Francisco José; González Jurado, José Antonio; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Motricidad Humana y Rendimiento Deportivo; Universidad de Sevilla. BIO271: Expresion Genica en Eucariontes
The impact of obesity on adipose tissue function is well acknowledged, but the role of physical exercise in regulating inflammatory markers and gene expression in obese individuals remains uncertain. This study aims to investigate the effects of chronic exercise on inflammatory gene expression in adipose tissue and to explore sex differences in response to exercise. The study involved 29 obese participants (13 men, 16 women) aged 38 to 54 years with a mean BMI of 36.05 ± 4.99 kg/m2. Participants underwent an 8-week concurrent training program comprising three weekly sessions of ~60 min each. The sessions included joint mobility exercises, cardiovascular activation, and cardiorespiratory resistance exercises at medium to low intensity. A fine-needle aspiration biopsy of abdominal subcutaneous adipose tissue was performed for gene expression analysis using quantitative polymerase chain reaction (qPCR). The study demonstrated that chronic exercise modulates the expression of pro-inflammatory genes in subcutaneous adipose tissue, particularly ADIPOR2 (p = 0.028), leptin (p = 0.041), and IFNg (p = 0.040) (downregulated). Interestingly, regardless of sex, the exercise programs had an independent effect on pro-inflammatory genes. Overall, this study provides insight into the role of chronic exercise in modulating adipose tissue gene expression in obese individuals. Further research involving both sexes is recommended to tailor exercise interventions for better outcomes.
Protein sorting upon exit from the endoplasmic reticulum dominates Golgi biogenesis in budding yeast
(Willey, 2023-02-24) Sasaki, Saku; Schlarmann, Philipp; Hanaoka, Kazuki; Nishii, Hinako; Moriya, Hisao; Muñiz Guinea, Manuel; Funato, Kouichi; Universidad de Sevilla. Departamento de Biología Celular; Japan Society for the Promotion of Science (JSPS). Japan; Agencia Estatal de Investigación. España; Junta de Andalucía; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Cells sense and control the number and quality of their organelles, but the underlying mechanisms of this regulation are not understood. Our recent research in the yeast Saccharomyces cerevisiae has shown that long acyl chain ceramides in the endoplasmic reticulum (ER) membrane and the lipid moiety of glycosylphosphatidylinositol (GPI) anchor determine the sorting of GPI-anchored proteins in the ER. Here, we show that a mutant strain, which produces shorter ceramides than the wild-type strain, displays a different count of Golgi cisternae. Moreover, deletions of proteins that remodel the lipid portion of GPI anchors resulted in an abnormal number of Golgi cisternae. Thus, our study reveals that protein sorting in the ER plays a critical role in maintaining Golgi biogenesis.
Sacha Inchi (Plukenetia volubilis L.) Protein Hydrolysate as a New Ingredient of Functional Foods
(MDPI, 2024) Lemus Conejo, Ana; Villanueva Lazo, Álvaro; Martín Rubio, María Esther; Millán, Francisco; Millán Linares , Carmen; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Ciencia, Innovación y Universidades (MICINN). España
Sacha inchi (Plukenetia volubilis L.) is an under-exploited crop with great potential due to its nutritional and medicinal characteristics. A Sacha inchi protein isolate (SII), obtained from defatted Sacha inchi flour (SIF), was hydrolyzed by Bioprotease LA 660 under specific conditions. The hydrolysates were characterized chemically, and their digestibility and antioxidant capacity were evaluated by in vitro cell-free experiments to select the hydrolysate with major antioxidant activity. Sacha inchi protein hydrolysate at 20 min (SIH20B) was selected, and the anti-inflammatory capacity was evaluated by RT-qPCR and ELISA techniques, using two different doses in monocytes THP-1 stimulated with lipopolysaccharide (LPS). The results obtained showed that the in vitro administration of SIH20B down-regulated the TNF-α gene and reduced the release of this cytokine, whereas the anti-inflammatory cytokines IL-10 and IL-4 were up-regulated in LPS-stimulated monocytes and co-administrated with SIH20B. The peptides contained in SIH20B were identified, and the 20 more relatively abundant peptides with a mass by 1 kDa were subjected to in silico analysis to hypothesize those that could be responsible for the bioactivity reported in the hydrolysate. From the identified peptides, the peptides AAGALKKFL and LGVKFKGGL, among others, are proposed as the most biologically actives. In conclusion, SIH20B is a novel, natural source of high-value-added biopeptides that could be used as an ingredient in formulations of food or nutraceutical compounds.
UBE2D3 Facilitates NHEJ by Orchestrating ATM Signalling through Multi-level Control of RNF168
(Springer Nature, 2024) Yalçin, Zeliha; Lam, Shiu Yeung; Peuscher, Marieke H.; van der Torre, Jaco; Zhu, Sha; Iyengar, Prasanna V.; Salas Lloret, Daniel; de Krijger, Inge; Moatti, Nathalie; van der Lugt, Ruben; González Prieto, Román; Jacobs, Jacqueline J.L.; Universidad de Sevilla. Departamento de Biología Celular
Maintenance of genome integrity requires tight control of DNA damage response (DDR) signalling and repair, with phosphorylation and ubiquitination representing key elements. How these events are coordinated to achieve productive DNA repair remains elusive. Here we identify the ubiquitin-conjugating enzyme UBE2D3 as a regulator of ATM kinase-induced DDR that promotes non-homologous end-joining (NHEJ) at telomeres. UBE2D3 contributes to DDR-induced chromatin ubiquitination and recruitment of the NHEJ-promoting factor 53BP1, both mediated by RNF168 upon ATM activation. Additionally, UBE2D3 promotes NHEJ by limiting RNF168 accumulation and facilitating ATM-mediated phosphorylation of KAP1-S824. Mechanistically, defective KAP1-S824 phosphorylation and telomeric NHEJ upon UBE2D3-deficiency are linked to RNF168 hyperaccumulation and aberrant PP2A phosphatase activity. Together, our results identify UBE2D3 as a multi-level regulator of NHEJ that orchestrates ATM and RNF168 activities. Moreover, they reveal a negative regulatory circuit in the DDR that is constrained by UBE2D3 and consists of RNF168- and phosphatase-mediated restriction of KAP1 phosphorylation.
Rewiring of the epigenome and chromatin architecture by exogenously induced retinoic acid signaling during zebrafish embryonic development
(Oxford University Press, 2024-04-24) Moreno Oñate, Marta; Gallardo Fuentes, Lourdes; Martínez García, Pedro M.; Naranjo, Silvia; Jiménez Gancedo, Sandra; Tena, Juan J.; Santos Pereira, José María; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Ciencia e Innovación (MICIN). España; Excelencia María de Maeztu; Junta de Andalucía; Universidad de Sevilla
Retinoic acid (RA) is the ligand of RA receptors (RARs), transcription factors that bind to RA response elements. RA signaling is required for multiple processes during embryonic development, including body axis extension, hindbrain antero-posterior patterning and forelimb bud initiation. Although some RA target genes have been identified, little is known about the genome-wide effects of RA signaling during in vivo embryonic development. Here, we stimulate the RA pathway by treating zebrafish embryos with all-trans-RA (atRA) and use a combination of RNA-seq, ATAC-seq, ChIP-seq and HiChIP to gain insight into the molecular mechanisms by which exogenously induced RA signaling controls gene expression. We find that RA signaling is involved in anterior/posterior patterning, central nervous system development, and the transition from pluripotency to differentiation. AtRA treatment also alters chromatin accessibility during early development and promotes chromatin binding of RARαa and the RA targets Hoxb1b, Meis2b and Sox3, which cooperate in central nervous system development. Finally, we show that exogenous RA induces a rewiring of chromatin architecture, with alterations in chromatin 3D interactions involving target genes. Altogether, our findings identify genome-wide targets of RA signaling and provide a molecular mechanism by which developmental signaling pathways regulate target gene expression by altering chromatin topology.
Physical interactions between specifically regulated subpopulations of the MCM and RNR complexes prevent genetic instability
(Public Library of Science, 2024-05-22) Yáñez Vilches, Aurora; Romero, Antonia M.; Barrientos Moreno, Marta; Cruz, Esther; González Prieto, Román; Sharma, Sushma; Vertegaal, Alfred C.O.; Prado, Félix; Universidad de Sevilla. Departamento de Biología Celular
The helicase MCM and the ribonucleotide reductase RNR are the complexes that provide the substrates (ssDNA templates and dNTPs, respectively) for DNA replication. Here, we demonstrate that MCM interacts physically with RNR and some of its regulators, including the kinase Dun1. These physical interactions encompass small subpopulations of MCM and RNR, are independent of the major subcellular locations of these two complexes, augment in response to DNA damage and, in the case of the Rnr2 and Rnr4 subunits of RNR, depend on Dun1. Partial disruption of the MCM/RNR interactions impairs the release of Rad52 -but not RPA-from the DNA repair centers despite the lesions are repaired, a phenotype that is associated with hypermutagenesis but not with alterations in the levels of dNTPs. These results suggest that a specifically regulated pool of MCM and RNR complexes plays noncanonical roles in genetic stability preventing persistent Rad52 centers and hypermutagenesis.
Roles of Extracellular Vesicles Associated Non-coding RNAs in Diabetes Mellitus
(Frontiers Media SA, 2022) Gauthier, B.R.; Cobo Vuilleumier, Nadia; López Noriega, Livia; Universidad de Sevilla. Departamento de Biología Celular; Junta de Andalucía; Ministerio de Economía y Competitividad (MINECO). España; Juvenile Diabetes Research Foundation (JDRF). USA
Extracellular vesicles (EVs), especially exosomes (50 to 150 nm), have been shown to play important roles in a wide range of physiological and pathological processes, including metabolic diseases such as Diabetes Mellitus (DM). In the last decade, several studies have demonstrated how EVs are involved in cell-to-cell communication. EVs are enriched in proteins, mRNAs and non-coding RNAs (miRNAs, long non-coding RNAs and circRNAS, among others) which are transferred to recipient cells and may have a profound impact in either their survival or functionality. Several studies have pointed out the contribution of exosomal miRNAs, such as miR-l42-3p and miR-26, in the development of Type 1 and Type 2 DM (T1DM and T2DM), respectively. In addition, some miRNA families such as miR-let7 and miR-29 found in exosomes have been associated with both types of diabetes, suggesting that they share common etiological features. The knowledge about the role of exosomal long non-coding RNAs in this group of diseases is more immature, but the exosomal lncRNA MALAT1 has been found to be elevated in the plasma of individuals with T2DM, while more than 169 lncRNAs were reported to be differentially expressed between healthy donors and people with T1DM. Here, we review the current knowledge about exosomal non-coding RNAs in DM and discuss their potential as novel biomarkers and possible therapeutic targets.
Physical Forces and Transient Nuclear Envelope Rupture During Metastasis: The Key for Success?
(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Gauthier, B.R.; Lorenzo, P.I.; Comaills, Valentine; Universidad de Sevilla. Departamento de Biología Celular; Asociación Española Contra el Cáncer (AECC); Junta de Andalucía; Ministerio de Economía y Competitividad (MINECO). España; Juvenile Diabetes Research Foundation (JDRF). USA
During metastasis, invading tumor cells and circulating tumor cells (CTC) face multiple mechanical challenges during migration through narrow pores and cell squeezing. However, little is known on the importance and consequences of mechanical stress for tumor progression and success in invading a new organ. Recently, several studies have shown that cell constriction can lead to nuclear envelope rupture (NER) during interphase. This loss of proper nuclear compartmentalization has a profound effect on the genome, being a key driver for the genome evolution needed for tumor progression. More than just being a source of genomic alterations, the transient nuclear envelope collapse can also support metastatic growth by several mechanisms involving the innate immune response cGAS/STING pathway. In this review we will describe the importance of the underestimated role of cellular squeezing in the progression of tumorigenesis. We will describe the complexity and difficulty for tumor cells to reach the metastatic site, detail the genomic aberration diversity due to NER, and highlight the importance of the activation of the innate immune pathway on cell survival. Cellular adaptation and nuclear deformation can be the key to the metastasis success in many unsuspected aspects.
NR5A2/LRH-1 Regulates the PTGS2-PGE2-PTGER1 Pathway Contributing to Pancreatic Islet Survival and Function
(Elsevier, 2022) Martin Vázquez, Eugenia; Cobo Vuilleumier, Nadia; Araujo Legido, Raquel; Marín Cañas, Sandra; Nola, Emanuele; Dorronsoro, Akaitz; López Bermudo, Lucía; Crespo, Alejandra; Romero Zerbo, Silvana Y.; Comaills, Valentine; Gauthier, Benoit R.; Universidad de Sevilla. Departamento de Biología Celular; Junta de Andalucía; Ministerio de Ciencia e Innovación (MICIN). España; Juvenile Diabetes Research Foundation. USA; Instituto de Salud Carlos III
LRH-1/NR5A2 is implicated in islet morphogenesis postnatally, and its activation using the agonist BL001 protects islets against apoptosis, reverting hyperglyce- mia in mouse models of Type 1 Diabetes Mellitus. Islet transcriptome profiling revealed that the expression of PTGS2/COX2 is increased by BL001. Herein, we sought to define the role of LRH-1 in postnatal islet morphogenesis and chart the BL001 mode of action conferring beta cell protection. LRH-1 ablation within developing beta cells impeded beta cell proliferation, correlating with mouse growth retardation, weight loss, and hypoglycemia leading to lethality. LRH-1 deletion in adult beta cells abolished the BL001 antidiabetic action, correlating with beta cell destruction and blunted Ptgs2 induction. Islet PTGS2 inactivation led to reduced PGE 2 levels and loss of BL001 protection against cytokines as evidenced by increased cytochrome c release and cleaved-PARP. The PTGER1 antagonist—ONO-8130—negated BL001-mediated islet survival. Our results define the LRH-1/PTGS2/PGE 2 /PTGER1 signaling axis as a key pathway medi- ating BL001 survival properties.
The PTGS2/COX2-PGE2 Signaling Cascade in Inflammation: Pro or Anti? A Case Study with Type 1 Diabetes Mellitus
(Ivyspring International Publisher, 2023) Martín Vázquez, Eugenia; Cobo Vuilleumier, Nadia; López Noriega, Livia; Lorenzo, Petra I.; Gauthier, Benoit R.; Universidad de Sevilla. Departamento de Biología Celular; Junta de Andalucía; Ministerio de Ciencia e Innovación (MICIN). España; Juvenile Diabetes Research Foundation. USA
Prostaglandins are lipid mediators involved in physiological processes, such as constriction or dilation of blood vessels, but also pathophysiological processes, which include inflammation, pain and fever. They are produced by almost all cell types in the organism by activation of Prostaglandin endoperoxide synthases/Cyclooxygenases. The inducible Prostaglandin Endoperoxide Synthase 2/Cyclooxygenase 2 (PTGS2/COX2) plays an important role in pathologies associated with inflammatory signaling. The main product derived from PTGS2/COX2 expression and activation is Prostaglandin E2 (PGE2), which promotes a wide variety of tissue-specific effects, pending environmental inputs. One of the major sources of PGE2 are infiltrating inflammatory cells - the production of this molecule increases drastically in damaged tissues. Immune infiltration is a hallmark of type 1 diabetes mellitus, a multifactorial disease that leads to autoimmune-mediated pancreatic beta cell destruction. Controversial effects for the PTGS2/COX2-PGE2 signaling cascade in pancreatic islet cells subjected to diabetogenic conditions have been reported, allocating PGE2 as both, cause and consequence of inflammation. Herein, we review the main effects of this molecular pathway in a tissue-specific manner, with a special emphasis on beta cell mass protection/destruction and its potential role in the prevention or development of T1DM. We also discuss strategies to target this pathway for future therapies.
Metabolic Reprogramming by Acly Inhibition Using SB-204990 Alters Glucoregulation and Modulates Molecular Mechanisms Associated with Aging
(Springer Nature, 2023) Sola García, Alejandro; Cáliz Molina, María Ángeles; Espadas, Isabel; Petr, Michael; Panadero Morón, Concepción; González Morán, Daniel; Martín Vázquez, María Eugenia; Narbona Pérez, Álvaro Jesús; López Noriega, Livia; Martínez Corrales, Guillermo; Martín Montalvo, Alejandro; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Economía y Competitividad (MINECO). España; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía; Consejo Superior de Investigaciones Científicas (CSIC); Nordea Foundation. Dinamarca; Novo Nordisk Foundation. Dinamarca; Lundbeck Foundation. Dinamarca; Ministry of Higher Education and Science of Denmark; Instituto de Salud Carlos III
ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.
Enzyme-Responsive Zr-Based Metal-Organic Frameworks for Controlled Drug Delivery: Taking Advantage of Clickable PEG-Phosphate Ligands
(American Chemical Society, 2023) Carrillo Carrión, Carolina; Comaills, Valentine; Visiga, Ana M.; Gauthier, Benoit R.; Khiar, Noureddine; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía; Asociación Española Contra el Cáncer; Marie Sklodowska-Curie Individual Fellowship; European Cooperation in Science and Technology (COST)
We report for the first time the controlled drug release from a nanoscale Zr-based metal-organic framework (MOF), UiO-66, in the presence of the enzyme alkaline phosphatase (ALP). This unprecedented reactivity was possible thanks to the prior functionalization of the MOF with N3-PEG-PO3 ligands, which were designed for three specific aims: (1) to impart colloidal stability in phosphate-containing media; (2) to endow the MOF with multifunctionality thanks to azide groups for the covalent attachment of an imaging agent by click-chemistry; and (3) to confer stimuli-responsive properties, specifically the selective release of doxorubicin triggered by the enzymatic activity of ALP. Cell studies revealed that the functionalization of the MOF with N3-(PEG)20-PO3 ligands improved their intracellular stability and led to a sustained drug release compared to the bare MOF. More importantly, an enhanced drug release was observed in cells with higher expression of ALP genes (HeLa versus MDA-MB-231 and MCF7), confirming the ALP-responsiveness of the system inside living cells.
dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe
(Springer Nature, 2024-05-14) Rodrigues, Joana S.; Chenlo, Miguel; Bravo, Susana B.; Pérez Romero, Sihara; Suárez Fariña, María; Sobrino, Tomás; Sanz Pamplona, Rebeca; González Prieto, Román; Álvarez, Clara V.; Universidad de Sevilla. Departamento de Biología Celular; Agencia Estatal de Investigación. España; Instituto de Salud Carlos III
The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with high mortality. We show here that depletion of the PIAS2 beta isoform with a transcribed double-stranded RNA–directed RNA interference (PIAS2b-dsRNAi) specifically inhibits growth of ATC cell lines and patient primary cultures in vitro and of orthotopic patient-derived xenografts (oPDX) in vivo. Critically, PIAS2b-dsRNAi does not affect growth of normal or non-anaplastic thyroid tumor cultures (differentiated carcinoma, benign lesions) or cell lines. PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. PIAS2b depletion promotes mitotic catastrophe at prophase. High-throughput proteomics reveals the proteasome (PSMC5) and spindle cytoskeleton (TUBB3) to be direct targets of PIAS2b SUMOylation at mitotic initiation. These results identify PIAS2b-dsRNAi as a promising therapy for ATC and other aggressive anaplastic carcinomas.

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