Grupos de investigación

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/19571

Browse

Now showing 1 - 20 of 69

Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells.
(NATURE PORTFOLIO, 2021-07) Casanova-Acebes, Maria; Dalla, Erica; Leader, Andrew M; LeBerichel, Jessica; Nikolic, Jovan; Morales, Blanca M; Brown, Markus; Chang, Christie; Troncoso, Leanna; Chen, Steven T; Sastre-Perona, Ana; Park, Matthew D; Tabachnikova, Alexandra; Dhainaut, Maxime; Hamon, Pauline; Maier, Barbara; Sawai, Catherine M; Agulló-Pascual, Esperanza; Schober, Markus; Brown, Brian D; Reizis, Boris; Marron, Thomas; Kenigsberg, Ephraim; Moussion, Christine; Benaroch, Philippe; Aguirre-Ghiso, Julio A; Merad, Miriam
Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial-mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8 T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.
Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition.
(CELL PRESS, 2016-04-19) Salmon, Hélène; Idoyaga, Juliana; Rahman, Adeeb; Leboeuf, Marylène; Remark, Romain; Jordan, Stefan; Casanova-Acebes, Maria; Khudoynazarova, Makhzuna; Agudo, Judith; Tung, Navpreet; Chakarov, Svetoslav; Rivera, Christina; Hogstad, Brandon; Bosenberg, Marcus; Hashimoto, Daigo; Gnjatic, Sacha; Bhardwaj, Nina; Palucka, Anna Karolina; Brown, Brian D; Brody, Joshua; Ginhoux, Florent; Merad, Miriam
Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen-presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103(+) dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8(+) T cells. CD103(+) DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the growth factor FLT3L followed by intratumoral poly I:C injections expanded and activated CD103(+) DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103(+) DCs in tumors limits checkpoint-blockade efficacy and combined FLT3L and poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade.
Innate immune cells as homeostatic regulators of the hematopoietic niche.
(Springuer, 2014-06) Casanova-Acebes, Maria; A-González, Noelia; Weiss, Linnea A; Hidalgo, Andrés
Two cellular systems of paramount importance for mammalian physiology, the myeloid and the hematopoietic, have received a great deal of attention in the past decade. Myeloid leukocytes, classically involved in mediating innate immune responses, are now known to regulate other important aspects of the organism's physiology, from development to regulation of metabolic functions. In parallel, many diverse cellular and molecular components have been identified in the bone marrow (BM) that are required for the regulation and lifelong preservation of hematopoietic stem and progenitor cells (HSPC). Since the production of blood and immune elements by these multipotent cells responds to environmental signals, it is not entirely surprising that the hematopoietic niches in which HSPC are located can in turn be regulated by the immune system. We review here recent evidence demonstrating that two components of the innate immune system, macrophages and neutrophils, regulate the function of the hematopoietic niche in ways that may favor both the retention and the release of HSPC from the BM. We propose that the highly migratory nature of neutrophils, the presence of a network of tissue-resident macrophages in the BM and possibly in other tissues, and the superb capacity of these innate immune cells to respond to stress endow them with regulatory functions that are ultimately relayed to the hematopoietic niche.
Serum is required for release of Alzheimer's amyloid precursor protein in neuroblastoma cells.
(PERGAMON-ELSEVIER SCIENCE LTD, 2002-10) Villa, Ana; Santiago, Jorge; García-Silva, Susana; Ruiz-León, Yolanda; Pascual, Angel
The beta-amyloid peptide, the major component of the senile plaques that characterize Alzheimer's disease, is generated from a set of alternatively spliced beta-amyloid precursor proteins (APPs), which are proteolytically cleaved by the action of a set of enzymes referred to generically as secretases. The major processing pathway involves the proteolytic cleavage of APP by alpha-secretase and results in the release of soluble non-amyloidogenic full-length amino terminal fragments (sAPP), which appear to be involved in neurotrophic events. A reduced production of these neuroprotective sAPP would contribute, together with deposition of the beta-amyloid peptide, to the neurodegenerative processes that lead to the cellular death in Alzheimer's disease. In the present work, we describe a dramatic reduction of sAPP content in medium conditioned by neuronal cells grown under low-serum conditions, when compared with the levels released in the presence of 10% serum. The inhibitory effect on sAPP release appears to be quite specific since that reduction occurs without major changes in cell proliferation, expression of APP-mRNA or intracellular APP levels. Under low-serum conditions, cells showed a more differentiated morphology and no apoptotic signs were observed. Since the alpha-secretase has been described as a membrane anchored protein, our results suggest that the serum contains an essential factor(s) involved in the alpha-secretase activity.
Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment.
(BMJ PUBLISHING GROUP, 2015-12) Sainz, Bruno; Alcala, Sonia; Garcia, Elena; Sanchez-Ripoll, Yolanda; Azevedo, Maria M; Cioffi, Michele; Tatari, Marianthi; Miranda-Lorenzo, Irene; Hidalgo, Manuel; Gomez-Lopez, Gonzalo; Cañamero, Marta; Erkan, Mert; Kleeff, Jörg; García-Silva, Susana; Sancho, Patricia; Hermann, Patrick C; Heeschen, Christopher
The tumour stroma/microenvironment not only provides structural support for tumour development, but more importantly it provides cues to cancer stem cells (CSCs) that regulate their self-renewal and metastatic potential. This is certainly true for pancreatic ductal adenocarcinomas (PDAC), where tumour-associated fibroblasts, pancreatic stellate cells and immune cells create an abundant paracrine niche for CSCs via microenvironment-secreted factors. Thus understanding the role that tumour stroma cells play in PDAC development and CSC biology is of utmost importance.
Hypothyroidism enhances tumor invasiveness and metastasis development.
(PUBLIC LIBRARY SCIENCE, 2009-07-29) Martínez-Iglesias, Olaia; García-Silva, Susana; Regadera, Javier; Aranda, Ana
Whereas there is increasing evidence that loss of expression and/or function of the thyroid hormone receptors (TRs) could result in a selective advantage for tumor development, the relationship between thyroid hormone levels and human cancer is a controversial issue. It has been reported that hypothyroidism might be a possible risk factor for liver and breast cancer in humans, but a lower incidence of breast carcinoma has been also reported in hypothyroid patients
Distinct C/EBPalpha motifs regulate lipogenic and gluconeogenic gene expression in vivo.
(SPRINGERNATURE, 2007-02-21) Pedersen, Thomas A; Bereshchenko, Oxana; Garcia-Silva, Susana; Ermakova, Olga; Kurz, Elke; Mandrup, Susanne; Porse, Bo T; Nerlov, Claus
The C/EBPalpha transcription factor regulates hepatic nitrogen, glucose, lipid and iron metabolism. However, how it is able to independently control these processes is not known. Here, we use mouse knock-in mutagenesis to identify C/EBPalpha domains that specifically regulate hepatic gluconeogenesis and lipogenesis. In vivo deletion of a proline-histidine rich domain (PHR), dephosphorylated at S193 by insulin signaling, dysregulated genes involved in the generation of acetyl-CoA and NADPH for triglyceride synthesis and led to increased hepatic lipogenesis. These promoters bound SREBP-1 as well as C/EBPalpha, and the PHR was required for C/EBPalpha-SREBP transcriptional synergy. In contrast, the highly conserved C/EBPalpha CR4 domain was found to undergo liver-specific dephosphorylation of residues T222 and T226 upon fasting, and alanine mutation of these residues upregulated the hepatic expression of the gluconeogenic G6Pase and PEPCK mRNAs, but not PGC-1alpha, leading to glucose intolerance. Our results show that pathway-specific metabolic regulation can be achieved through a single transcription factor containing context-sensitive regulatory domains, and indicate C/EBPalpha phosphorylation as a PGC-1alpha-independent mechanism for regulating hepatic gluconeogenesis.
Molecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information.
(SPRINGERNATURE, 2008-03-06) Montero-Conde, Cristina; Martín-Campos, J M; Lerma, E; Gimenez, G; Martínez-Guitarte, J L; Combalía, N; Montaner, D; Matías-Guiu, X; Dopazo, J; de Leiva, A; Robledo Batanero, Mercedes; Mauricio, D
Undifferentiated and poorly differentiated thyroid tumors are responsible for more than half of thyroid cancer patient deaths in spite of their low incidence. Conventional treatments do not obtain substantial benefits, and the lack of alternative approaches limits patient survival. Additionally, the absence of prognostic markers for well-differentiated tumors complicates patient-specific treatments and favors the progression of recurrent forms. In order to recognize the molecular basis involved in tumor dedifferentiation and identify potential markers for thyroid cancer prognosis prediction, we analysed the expression profile of 44 thyroid primary tumors with different degrees of dedifferentiation and aggressiveness using cDNA microarrays. Transcriptome comparison of dedifferentiated and well-differentiated thyroid tumors identified 1031 genes with >2-fold difference in absolute values and false discovery rate of <0.15. According to known molecular interaction and reaction networks, the products of these genes were mainly clustered in the MAPkinase signaling pathway, the TGF-beta signaling pathway, focal adhesion and cell motility, activation of actin polymerization and cell cycle. An exhaustive search in several databases allowed us to identify various members of the matrix metalloproteinase, melanoma antigen A and collagen gene families within the upregulated gene set. We also identified a prognosis classifier comprising just 30 transcripts with an overall accuracy of 95%. These findings may clarify the molecular mechanisms involved in thyroid tumor dedifferentiation and provide a potential prognosis predictor as well as targets for new therapies.
Association study of 69 genes in the ret pathway identifies low-penetrance loci in sporadic medullary thyroid carcinoma.
(AMER ASSOC CANCER RESEARCH, 2007-10-01) Montero-Conde, Cristina; Ruiz-Llorente, Sergio; Montero-Conde, Cristina; Milne, Roger L; Moya, Christian M; Cebrián, Arancha; Letón, Rocío; Cascón, Alberto; Mercadillo, Fátima; Landa, Iñigo; Borrego, Salud; Pérez de Nanclares, Guiomar; Alvarez-Escolá, Cristina; Díaz-Pérez, José Angel; Carracedo, Angel; Urioste, Miguel; González-Neira, Anna; Benítez, Javier; Santisteban, Pilar; Dopazo, Joaquín; Ponder, Bruce A; Robledo Batanero, Mercedes
To date, few association studies have been done to better understand the genetic basis for the development of sporadic medullary thyroid carcinoma (sMTC). To identify additional low-penetrance genes, we have done a two-stage case-control study in two European populations using high-throughput genotyping. We selected 417 single nucleotide polymorphisms (SNP) belonging to 69 genes either related to RET signaling pathway/functions or involved in key processes for cancer development. TagSNPs and functional variants were included where possible. These SNPs were initially studied in the largest known series of sMTC cases (n = 266) and controls (n = 422), all of Spanish origin. In stage II, an independent British series of 155 sMTC patients and 531 controls was included to validate the previous results. Associations were assessed by an exhaustive analysis of individual SNPs but also considering gene- and linkage disequilibrium-based haplotypes. This strategy allowed us to identify seven low-penetrance genes, six of them (STAT1, AURKA, BCL2, CDKN2B, CDK6, and COMT) consistently associated with sMTC risk in the two case-control series and a seventh (HRAS) with individual SNPs and haplotypes associated with sMTC in the Spanish data set. The potential role of CDKN2B was confirmed by a functional assay showing a role of a SNP (rs7044859) in the promoter region in altering the binding of the transcription factor HNF1. These results highlight the utility of association studies using homogeneous series of cases for better understanding complex diseases.
Allelic variant at -79 (C>T) in CDKN1B (p27Kip1) confers an increased risk of thyroid cancer and alters mRNA levels.
(BIOSCIENTIFICA LTD, 2010-06) Landa, Iñigo; Montero-Conde, Cristina; Malanga, Donatella; De Gisi, Silvia; Pita, Guillermo; Leandro-García, Luis-Javier; Inglada-Pérez, Lucía; Letón, Rocío; De Marco, Carmela; Rodriguez Antona, Cristina; Viglietto, Giuseppe; Robledo, Mercedes; Robledo Batanero, Mercedes; Instituto de Salud Carlos III; Fondazione AIRC per la ricerca sul cancro; Fondazione AIRC per la ricerca sul cancro; CIBERER
The aim of this study is to assess if common genetic variants located in the CDKN1B locus, coding for the cell cycle inhibitor p27(Kip1), are involved in thyroid cancer susceptibility. Based on the literature and functional predictions, we selected three polymorphisms within the CDKN1B gene (rs2066827 (T326G, V109G), rs34330 (-79C>T) and rs36228499 (-838C>A)) to perform the first case-control study in thyroid cancer involving this locus. We had 649 Spanish patients with sporadic thyroid cancer and 385 healthy representative controls available. Luciferase reporter gene assays, real-time quantitative reverse transcription-PCR and immunoblot experiments were carried out to demonstrate the putative effect of the associated variant. The polymorphism rs34330 (-79C>T) was identified as a risk factor for developing the follicular variant of papillary thyroid carcinoma (FVPTC), fitting a recessive model (odds ratio=2.12; 95% confidence interval=1.09-4.15; P value=0.023). The risk allele (T) of this single nucleotide polymorphism led to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27(Kip1) promoter (P value <0.001). This effect was observed in -79TT genotype control carriers, who showed a tendency towards lower CDKN1B mRNA levels in lymphocytes, as well as at the protein level. This is the first study that identifies CDKN1B as a low-penetrance gene in thyroid cancer, and specifically in FVPTC subtype. We propose a reduced CDKN1B gene transcription depending on the genotype of the -79C>T (rs34330) variant as a novel mechanism underlying p27(Kip1) downregulation.
Increased Global DNA Hypomethylation in Distant Metastatic and Dedifferentiated Thyroid Cancer.
(Endocrine Society, 2018-02-01) Klein Hesselink, Esther N; Zafon, Carles; Villalmanzo, Núria; Iglesias, Carmela; van Hemel, Bettien M; Klein Hesselink, Mariëlle S; Montero-Conde, Cristina; Buj, Raquel; Mauricio, Dídac; Peinado, Miguel A; Puig-Domingo, Manel; Riesco-Eizaguirre, Garcilaso; Reverter, Jordi L; Robledo Batanero, Mercedes; Links, Thera P; Jordà, Mireia; European Regional Development Fund; Instituto de Salud Carlos III; Ministerio de Economia y Competitividad (España); Nijbakker-Morra Fonds; Asociación Española contra el Cáncer
Global DNA hypomethylation is a major event for the development and progression of cancer, although the significance in thyroid cancer remains unclear. Therefore, we aimed to investigate its role in thyroid cancer progression and its potential as a prognostic marker.
Reduced stent strategy versus conventional percutaneous coronary revascularization in patients presenting with STEMI: the COPERNICAN trial.
(Ediciones Doyma, 2025-05-22) Sanz-Sánchez, Jorge; Santos Martínez, Sandra; Rumiz González, Eva; Oteo Domínguez, Juan Francisco; Tejada Ponce, David; Gómez Menchero, Antonio; Sánchez Elvira, Guillermo; Fuertes Ferre, Georgina; Rivero Crespo, Fernando; Lukic Otanovic, Antonela; Díaz Fernández, José; Galindo Fernández, Eladio; Urbano Carrillo, Cristóbal; Salvatella Giralt, Neus; Torres Sánchez, Mauricio; García Touchard, Arturo; Ibáñez Cabeza, Borja; Stefanini, Giulio; Alfonso Manterola, Fernando; García García, Héctor; Amat-Santos, Ignacio J
Primary percutaneous coronary intervention (PCI) with drug-eluting stent implantation (DES) is the standard of treatment in patients presenting with ST-segment elevation myocardial infarction (STEMI). However, target lesion failure can occur due to stent underexpansion, malapposition, hypersensitivity, fracture, and neoatherosclerosis. Drug-coated balloons (DCB) represent a potential alternative supported by the concept of "leaving nothing behind." The aim is to compare a reduced stent strategy based on DCB- with DES-PCI in patients presenting with STEMI. Prospective, pragmatic, multicenter, noninferiority, randomized clinical trial. A total of 1 272 patients presenting with STEMI will be randomized to any paclitaxel-DCB vs any sirolimus-DES (both with CE approval) for all culprit and nonculprit lesions during PCI. The primary endpoint will be target-lesion failure: cardiac death, target-vessel myocardial infarction, or ischemia-driven target lesion revascularization at 12-month follow-up. An independent clinical events committee masked to treatment allocation will adjudicate all suspected events. Clinical follow-up will be performed after 1 month (30 days±5 days) and 1 year (365 days±30 days). An extended follow-up at 3, 5, and 10 years is planned. The COPERNICAN trial will be the first randomized study comparing clinical outcomes of DCB vs DES in STEMI patients.
A mouse model to identify cooperating signaling pathways in cancer.
(Springuer Nature, 2012-09) Musteanu, Mónica; Blaas, Leander; Zenz, Rainer; Svinka, Jasmin; Hoffmann, Thomas; Grabner, Beatrice; Schramek, Daniel; Kantner, Hans-Peter; Müller, Mathias; Kolbe, Thomas; Rülicke, Thomas; Moriggl, Richard; Kenner, Lukas; Stoiber, Dagmar; Penninger, Josef Martin; Popper, Helmut; Casanova, Emilio; Eferl, Robert; European Research Council (ERC); Institute of Molecular Biotechnology (IMBA); Austrian Science Fund (FWF); Ludwig Boltzmann Gesellschaft (LBG)
We here establish a mouse cancer model called Multi-Hit that allows for the evaluation of oncogene cooperativities in tumor development. The model is based on the stochastic expression of oncogene combinations ('hits') that are mediated by Cre in a given tissue. Cells with cooperating hits are positively selected and give rise to tumors. We used this approach to evaluate the requirement of Ras downstream effector pathways in tumorigenesis.
Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity.
(Cell Press, 2023-06-08) Arora, Mansi; Moser, Justin; Hoffman, Timothy E; Watts, Lotte P; Min, Mingwei; Musteanu, Mónica; Rong, Yao; Ill, C Ryland; Nangia, Varuna; Schneider, Jordan; Sanclemente, Manuel; Lapek, John; Nguyen, Lisa; Niessen, Sherry; Dann, Stephen; VanArsdale, Todd; Barbacid, Mariano; Miller, Nichol; Spencer, Sabrina L; United States Department of Health & Human Services National Institutes of Health (NIH) - USA; Spencer Lab from University of Colorado-Boulder; Pfizer
CDK2 is a core cell-cycle kinase that phosphorylates many substrates to drive progression through the cell cycle. CDK2 is hyperactivated in multiple cancers and is therefore an attractive therapeutic target. Here, we use several CDK2 inhibitors in clinical development to interrogate CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation in preclinical models. Whereas CDK1 is known to compensate for loss of CDK2 in Cdk2 mice, this is not true of acute inhibition of CDK2. Upon CDK2 inhibition, cells exhibit a rapid loss of substrate phosphorylation that rebounds within several hours. CDK4/6 activity backstops inhibition of CDK2 and sustains the proliferative program by maintaining Rb1 hyperphosphorylation, active E2F transcription, and cyclin A2 expression, enabling re-activation of CDK2 in the presence of drug. Our results augment our understanding of CDK plasticity and indicate that co-inhibition of CDK2 and CDK4/6 may be required to suppress adaptation to CDK2 inhibitors currently under clinical assessment.
CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study.
(Wiley, 2023-03-01) Kang, Eun-Young; Weir, Ashley; Meagher, Nicola S; Farrington, Kyo; Nelson, Gregg S; Ghatage, Prafull; Lee, Cheng-Han; Riggan, Marjorie J; Bolithon, Adelyn; Popovic, Gordana; Leung, Betty; Tang, Katrina; Lambie, Neil; Millstein, Joshua; Alsop, Jennifer; Anglesio, Michael S; Ataseven, Beyhan; Barlow, Ellen; Beckmann, Matthias W; Berger, Jessica; Bisinotto, Christiani; Bösmüller, Hans; Boros, Jessica; Brand, Alison H; Brooks-Wilson, Angela; Brucker, Sara Y; Carney, Michael E; Casablanca, Yovanni; Cazorla-Jiménez, Alicia; Cohen, Paul A; Conrads, Thomas P; Cook, Linda S; Coulson, Penny; Courtney-Brooks, Madeleine; Cramer, Daniel W; Crowe, Philip; Cunningham, Julie M; Cybulski, Cezary; Darcy, Kathleen M; El-Bahrawy, Mona A; Elishaev, Esther; Erber, Ramona; Farrell, Rhonda; Fereday, Sian; Fischer, Anna; García, María J; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Gilks, C Blake; Grube, Marcel; Harnett, Paul R; Harrington, Shariska Petersen; Harter, Philipp; Hartmann, Arndt; Hecht, Jonathan L; Heikaus, Sebastian; Hein, Alexander; Heitz, Florian; Hendley, Joy; Hernandez, Brenda Y; Polo, Susanna Hernando; Heublein, Sabine; Hirasawa, Akira; Høgdall, Estrid; Høgdall, Claus K; Horlings, Hugo M; Huntsman, David G; Huzarski, Tomasz; Jewell, Andrea; Jimenez-Linan, Mercedes; Jones, Michael E; Kaufmann, Scott H; Kennedy, Catherine J; Khabele, Dineo; Kommoss, Felix K F; Kruitwagen, Roy F P M; Lambrechts, Diether; Le, Nhu D; Lener, Marcin; Lester, Jenny; Leung, Yee; Linder, Anna; Loverix, Liselore; Lubiński, Jan; Madan, Rashna; Maxwell, G Larry; Modugno, Francesmary; Neuhausen, Susan L; Olawaiye, Alexander; Olbrecht, Siel; Orsulic, Sandra; Palacios, José; Pearce, Celeste Leigh; Pike, Malcolm C; Quinn, Carmel M; Mohan, Ganendra Raj; Rodríguez-Antona, Cristina; Ruebner, Matthias; Ryan, Andy; Salfinger, Stuart G; Sasamoto, Naoko; Schildkraut, Joellen M; Schoemaker, Minouk J; Shah, Mitul; Sharma, Raghwa; Shvetsov, Yurii B; Singh, Naveena; Sonke, Gabe S; Steele, Linda; Stewart, Colin J R; Sundfeldt, Karin; Swerdlow, Anthony J; Talhouk, Aline; Tan, Adeline; Taylor, Sarah E; Terry, Kathryn L; Tołoczko, Aleksandra; Traficante, Nadia; Van de Vijver, Koen K; van der Aa, Maaike A; Van Gorp, Toon; Van Nieuwenhuysen, Els; van-Wagensveld, Lilian; Vergote, Ignace; Vierkant, Robert A; Wang, Chen; Wilkens, Lynne R; Winham, Stacey J; Wu, Anna H; Benitez, Javier; Berchuck, Andrew; Candido Dos Reis, Francisco J; DeFazio, Anna; Fasching, Peter A; Goode, Ellen L; Goodman, Marc T; Gronwald, Jacek; Karlan, Beth Y; Kommoss, Stefan; Menon, Usha; Sinn, Hans-Peter; Staebler, Annette; Brenton, James D; Bowtell, David D; Pharoah, Paul D P; Ramus, Susan J; Köbel, Martin; National Health & Medical Research Council (NHMRC); Translational Cancer Research Network; United States Department of Health & Human Services National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Heuer Stiftung fur medizinische Forschung; Janet D. Cottrelle Foundation Scholars program; Michael Smith Foundation for Health Research; FWO; UK Research & Innovation (UKRI); German Research Foundation (DFG); Medical Research Council UK (MRC)
Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.
Effect of ionizing radiation in sensory ganglion neurons: organization and dynamics of nuclear compartments of DNA damage/repair and their relationship with transcription and cell cycle.
(Springuer, 2011-10) Casafont, Iñigo; Palanca, Ana; Lafarga, Vanesa; Berciano, Maria T; Lafarga, Miguel; Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas; COMUNIDAD DE CANTABRIA (ASTURIAS)
Neurons are very sensitive to DNA damage induced by endogenous and exogenous genotoxic agents, as defective DNA repair can lead to neurodevelopmental disorders, brain tumors and neurodegenerative diseases with severe clinical manifestations. Understanding the impact of DNA damage/repair mechanisms on the nuclear organization, particularly on the regulation of transcription and cell cycle, is essential to know the pathophysiology of defective DNA repair syndromes. In this work, we study the nuclear architecture and spatiotemporal organization of chromatin compartments involved in the DNA damage response (DDR) in rat sensory ganglion neurons exposed to X-ray irradiation (IR). We demonstrate that the neuronal DDR involves the formation of two categories of DNA-damage processing chromatin compartments: transient, disappearing within the 1 day post-IR, and persistent, where unrepaired DNA is accumulated. Both compartments concentrate components of the DDR pathway, including γH2AX, pATM and 53BP1. Furthermore, DNA damage does not induce neuronal apoptosis but triggers the G0-G1 cell cycle phase transition, which is mediated by the activation of the ATM-p53 pathway and increased protein levels of p21 and cyclin D1. Moreover, the run on transcription assay reveals a severe inhibition of transcription at 0.5 h post-IR, followed by its rapid recovery over the 1 day post-IR in parallel with the progression of DNA repair. Therefore, the response of healthy neurons to DNA damage involves a transcription- and cell cycle-dependent but apoptosis-independent process. Furthermore, we propose that the segregation of unrepaired DNA in a few persistent chromatin compartments preserves genomic stability of undamaged DNA and the global transcription rate in neurons.
Establishing and dissolving cohesion during the vertebrate cell cycle.
(Elsevier, 2018-06) Morales, Carmen; Losada, Ana; European Union (EU); Ministerio de Econonmía y Comptetividad (España); FEDER funds
Replicated chromatids are held together from the time they emerge from the replication fork until their separation in anaphase. This process, known as cohesion, promotes faithful DNA repair by homologous recombination in interphase and ensures accurate chromosome segregation in mitosis. Identification of cohesin thirty years ago solved a long-standing question about the nature of the linkage keeping together the sister chromatids. Cohesin is an evolutionarily conserved complex composed of a heterodimer of the Structural Maintenance of Chromosomes (SMC) family of ATPases, Smc1 and Smc3, the kleisin subunit Rad21 and a Huntingtin/EF3/PP2A/Tor1 (HEAT) repeat domain-containing subunit named SA/STAG. In addition to mediating cohesion, cohesin plays a major role in genome organization. Cohesin functions rely on the ability of the complex to entrap DNA topologically and in a dynamic manner. Establishment of cohesion during S phase requires coordination with the DNA replication machinery and restricts the dynamic behaviour of at least a fraction of cohesin. Dissolution of cohesion in subsequent mitosis is regulated by multiple mechanisms that ensure that daughter cells receive the correct number of intact chromosomes. We here review recent progress on our understanding of how these processes are regulated in somatic vertebrate cells.
MLL gene fusions in human leukaemias: in vivo modelling to recapitulate these primary tumourigenic events.
(Springuer, 2008-01) Rodriguez Perales, Sandra; Cano, F; Lobato, M N; Rabbitts, T H; UK Research & Innovation (UKRI); Medical Research Council UK (MRC)
Recurrent reciprocal chromosomal translocations are frequently found in leukaemias and sarcomas as initiating events in these cancers. Mouse models of chromosomal translocations are not only important for the elucidation of the mechanism of these factors underlying the disease but are also important pre-clinical models for assessing new drug combinations, developing new rational therapeutic strategies based on new drugs and testing novel macromolecular drugs. We describe three technologies for creating chromosomal translocation mimics in mice, applied specifically to understand how the MLL-fusions contribute to leukaemia. An important finding of this work is that the lineage of the tumours can be controlled by the MLL-protein fusion. The translocation mimic methods can be applied to any human reciprocal chromosomal translocation.
Peroxisome proliferator activated receptor gamma 2 modulates late pregnancy homeostatic metabolic adaptations.
(BMC, 2016-12) Vivas, Yurena; Díez-Hochleitner, Monica; Izquierdo-Lahuerta, Adriana; Corrales, Patricia; Horrillo, Daniel; Velasco, Ismael; Martínez-García, Cristina; Campbell, Mark; Sevillano, Julio; Ricote, Mercedes; Ros, Manuel; Ramos, Maria Pilar; Medina-Gomez, Gema
Pregnancy requires the adaptation of maternal energy metabolism including expansion and functional modifications of adipose tissue. Insulin resistance (IR), predominantly during late gestation, is a physiological metabolic adaptation that serves to support the metabolic demands of fetal growth. The molecular mechanisms underlying these adaptations are not fully understood and may contribute to gestational diabetes mellitus. Peroxisome proliferator-activated receptor gamma (PPARγ) controls adipogenesis, glucose and lipid metabolism and insulin sensitivity. The PPARγ2 isoform is mainly expressed in adipocytes and is thus likely to contribute to adipose tissue adaptation during late pregnancy. In the present study, we investigated the contribution of PPARγ2 to the metabolic adaptations occurring during the late phase of pregnancy in the context of IR. Using a model of late pregnancy in PPARγ2 knockout (KO) mice, we found that deletion of PPARγ2 exacerbated IR in association with lower serum adiponectin levels, increased body weight and enhanced lipid accumulation in liver. Lack of PPARγ2 provoked changes in the distribution of fat mass and preferentially prevented the expansion of the perigonadal depot while at the same time exacerbating inflammation. PPARγ2KO pregnant mice presented adipose tissue depot-dependent decreased expression of genes involved in lipid metabolism. Collectively, these data indicate that PPARγ2 is essential to promote healthy adipose tissue expansion and immune and metabolic functionality during pregnancy, contributing to the physiological adaptations that lead gestation to term.
Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model.
(The company of biologists, 2012-09) Martínez-García, Cristina; Izquierdo, Adriana; Velagapudi, Vidya; Vivas, Yurena; Velasco, Ismael; Campbell, Mark; Burling, Keith; Cava, Fernando; Ros, Manuel; Oresic, Matej; Vidal-Puig, Antonio; Medina-Gomez, Gema
Individuals with metabolic syndrome are at high risk of developing chronic kidney disease (CKD) through unclear pathogenic mechanisms. Obesity and diabetes are known to induce glucolipotoxic effects in metabolically relevant organs. However, the pathogenic role of glucolipotoxicity in the aetiology of diabetic nephropathy is debated. We generated a murine model, the POKO mouse, obtained by crossing the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) knockout (KO) mouse into a genetically obese ob/ob background. We have previously shown that the POKO mice showed: hyperphagia, insulin resistance, hyperglycaemia and dyslipidaemia as early as 4 weeks of age, and developed a complete loss of normal β-cell function by 16 weeks of age. Metabolic phenotyping of the POKO model has led to investigation of the structural and functional changes in the kidney and changes in blood pressure in these mice. Here we demonstrate that the POKO mouse is a model of renal disease that is accelerated by high levels of glucose and lipid accumulation. Similar to ob/ob mice, at 4 weeks of age these animals exhibited an increased urinary albumin:creatinine ratio and significantly increased blood pressure, but in contrast showed a significant increase in the renal hypertrophy index and an associated increase in p27(Kip1) expression compared with their obese littermates. Moreover, at 4 weeks of age POKO mice showed insulin resistance, an alteration of lipid metabolism and glomeruli damage associated with increased transforming growth factor beta (TGFβ) and parathyroid hormone-related protein (PTHrP) expression. At this age, levels of proinflammatory molecules, such as monocyte chemoattractant protein-1 (MCP-1), and fibrotic factors were also increased at the glomerular level compared with levels in ob/ob mice. At 12 weeks of age, renal damage was fully established. These data suggest an accelerated lesion through glucolipotoxic effects in the renal pathogenesis in POKO mice.

Browse

Recent Submissions