Person: Real Arribas, Francisco
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Francisco
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Real Arribas
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CNIO
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Publication Essential Roles of Cohesin STAG2 in Mouse Embryonic Development and Adult Tissue Homeostasis.(Cell Press, 2020-08-11) Lapi, Eleonora; Badia-Careaga, Claudio; CossÃo, Itziar; Giménez-Llorente, Daniel; RodrÃguez-Corsino, Miriam; Andrada, Elena; Hidalgo, Andres; Manzanares, Miguel; Real Arribas, Francisco; Losada, Ana; De Koninck, Magali; Unión Europea; Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España); Fundación ProCNICCohesin mediates sister chromatid cohesion and 3D genome folding. Two versions of the complex carrying STAG1 or STAG2 coexist in somatic vertebrate cells. STAG2 is commonly mutated in cancer, and germline mutations have been identified in cohesinopathy patients. To better understand the underlying pathogenic mechanisms, we report the consequences of Stag2 ablation in mice. STAG2 is largely dispensable in adults, and its tissue-wide inactivation does not lead to tumors but reduces fitness and affects both hematopoiesis and intestinal homeostasis. STAG2 is also dispensable for murine embryonic fibroblasts in vitro. In contrast, Stag2-null embryos die by mid-gestation and show global developmental delay and defective heart morphogenesis, most prominently in structures derived from secondary heart field progenitors. Both decreased proliferation and altered transcription of tissue-specific genes contribute to these defects. Our results provide compelling evidence on cell- and tissue-specific roles of different cohesin complexes and how their dysfunction contributes to disease.Publication Cell Lineage Infidelity in PDAC Progression and Therapy Resistance.(Frontiers Media, 2021) Malinova, Antonia; Veghini, Lisa; Real Arribas, Francisco; Corbo, Vincenzo; Associazione Italiana Ricerca sul Cancro; Marie Curie; Ministerio de Ciencia y Universidades (España)Infidelity to cell fate occurs when differentiated cells lose their original identity and either revert to a more multipotent state or transdifferentiate into a different cell type, either within the same embryonic lineage or in an entirely different one. Whilst in certain circumstances, such as in wound repair, this process is beneficial, it can be hijacked by cancer cells to drive disease initiation and progression. Cell phenotype switching has been shown to also serve as a mechanism of drug resistance in some epithelial cancers. In pancreatic ductal adenocarcinoma (PDAC), the role of lineage infidelity and phenotype switching is still unclear. Two consensus molecular subtypes of PDAC have been proposed that mainly reflect the existence of cell lineages with different degrees of fidelity to pancreatic endodermal precursors. Indeed, the classical subtype of PDAC is characterised by the expression of endodermal lineage specifying transcription factors, while the more aggressive basal-like/squamous subtype is defined by epigenetic downregulation of endodermal genes and alterations in chromatin modifiers. Here, we summarise the current knowledge of mechanisms (genetic and epigenetic) of cell fate switching in PDAC and discuss how pancreatic organoids might help increase our understanding of both cell-intrinsic and cell-extrinsic factors governing lineage infidelity during the distinct phases of PDAC evolution.Publication A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.(BioMed Central (BMC), 2021-02-01) López de Maturana, Evangelina; RodrÃguez, Juan Antonio; Alonso, Lola; Lao, Oscar; Molina-Montes, Esther; MartÃn-Antoniano, Isabel Adoración; Gómez-Rubio, Paulina; Lawlor, Rita; Carrato, Alfredo; Hidalgo, Manuel; Iglesias, Mar; Molero, Xavier; Löhr, Matthias; Michalski, Christopher; Perea, José; O'Rorke, Michael; Barberà , Victor Manuel; Tardón, Adonina; Farré, Antoni; Muñoz-BellvÃs, LuÃs; Crnogorac-Jurcevic, Tanja; DomÃnguez-Muñoz, Enrique; Gress, Thomas; Greenhalf, William; Sharp, Linda; Arnes, LuÃs; Cecchini, LluÃs; Balsells, Joaquim; Costello, Eithne; Ilzarbe, Lucas; Kleeff, Jörg; Kong, Bo; Márquez, Mirari; Mora, Josefina; O'Driscoll, Damian; Scarpa, Aldo; Ye, Weimin; Yu, Jingru; GarcÃa-Closas, Montserrat; Kogevinas, Manolis; Rothman, Nathaniel; Silverman, Debra T; Albanes, Demetrius; Arslan, Alan A; Beane-Freeman, Laura; Bracci, Paige M; Brennan, Paul; Bueno-de-Mesquita, Bas; Buring, Julie; Canzian, Federico; Du, Margaret; Gallinger, Steve; Gaziano, J Michael; Goodman, Phyllis J; Gunter, Marc; LeMarchand, Loic; Li, Donghui; Neale, Rachael E; Peters, Ulrika; Petersen, Gloria M; Risch, Harvey A; Sánchez, Maria José; Shu, Xiao-Ou; Thornquist, Mark D; Visvanathan, Kala; Zheng, Wei; Chanock, Stephen J; Easton, Douglas; Wolpin, Brian M; Stolzenberg-Solomon, Rachael Z; Klein, Alison P; Amundadottir, Laufey T; Marti-Renom, Marc A; Real Arribas, Francisco; Malats, Nuria; Instituto de Salud Carlos III; Asociación Española Contra el Cáncer; Unión Europea. European Cooperation in Science and Technology (COST).; Unión Europea; NIH - National Cancer Institute (NCI) (Estados Unidos)BACKGROUND Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. METHODS We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. RESULTS We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support. CONCLUSIONS This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.Publication STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells.(Oxford University Press, 2021-11-08) Richart, Laia; Lapi, Eleonora; Pancaldi, Vera; Cuenca-Ardura, Mirabai; Pau, Enrique Carrillo-de-Santa; Madrid-MencÃa, Miguel; Neyret-Kahn, Hélène; Radvanyi, François; RodrÃguez, Juan Antonio; Cuartero, Yasmina; Serra, François; Le Dily, François; Valencia, Alfonso; Marti-Renom, Marc A; Real Arribas, Francisco; Asociación Española Contra el Cáncer; Institut National de la Santé et de la Recherche Médicale (Francia); Fondation Toulouse Cancer Sante; Ministerio de Ciencia, Innovación y Universidades (España); Institució Catalana de Recerca i Estudis Avançats; Government of Catalonia (España); Unión Europea. Comisión Europea; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Cohesin exists in two variants containing STAG1 or STAG2. STAG2 is one of the most mutated genes in cancer and a major bladder tumor suppressor. Little is known about how its inactivation contributes to tumorigenesis. Here, we analyze the genomic distribution of STAG1 and STAG2 and perform STAG2 loss-of-function experiments using RT112 bladder cancer cells; we then analyze the genomic effects by integrating gene expression and chromatin interaction data. Functional compartmentalization exists between the cohesin complexes: cohesin-STAG2 displays a distinctive genomic distribution and mediates short and mid-ranged interactions that engage genes at higher frequency than those established by cohesin-STAG1. STAG2 knockdown results in down-regulation of the luminal urothelial signature and up-regulation of the basal transcriptional program, mirroring differences between STAG2-high and STAG2-low human bladder tumors. This is accompanied by rewiring of DNA contacts within topological domains, while compartments and domain boundaries remain refractive. Contacts lost upon depletion of STAG2 are assortative, preferentially occur within silent chromatin domains, and are associated with de-repression of lineage-specifying genes. Our findings indicate that STAG2 participates in the DNA looping that keeps the basal transcriptional program silent and thus sustains the luminal program. This mechanism may contribute to the tumor suppressor function of STAG2 in the urothelium.Publication An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer.(Nature Publishing Group, 2021-04-16) Lindskrog, Sia Viborg; Prip, Frederik; Lamy, Philippe; Taber, Ann; Groeneveld, Clarice S; Birkenkamp-Demtröder, Karin; Jensen, Jørgen Bjerggaard; Strandgaard, Trine; Nordentoft, Iver; Christensen, Emil; Sokac, Mateo; Birkbak, Nicolai J; Maretty, Lasse; Hermann, Gregers G; Petersen, Astrid C; Weyerer, Veronika; Grimm, Marc-Oliver; Horstmann, Marcus; Sjödahl, Gottfrid; Höglund, Mattias; Steiniche, Torben; Mogensen, Karin; de Reyniès, Aurélien; Nawroth, Roman; Jordan, Brian; Lin, Xiaoqi; Dragicevic, Dejan; Ward, Douglas G; Goel, Anshita; Hurst, Carolyn D; Raman, Jay D; Warrick, Joshua I; Segersten, Ulrika; Sikic, Danijel; van Kessel, Kim E M; Maurer, Tobias; Meeks, Joshua J; DeGraff, David J; Bryan, Richard T; Knowles, Margaret A; Simic, Tatjana; Hartmann, Arndt; Zwarthoff, Ellen C; Malmström, Per-Uno; Malats, Núria; Real Arribas, Francisco; Dyrskjøt, Lars; Aarhus University (Dinamarca); Health Research Foundation of Central Denmark Region; Danish Cancer Society; Instituto de Salud Carlos III; Asociación Española Contra el Cáncer; American Cancer Society; United States Department of DefenseThe molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.Publication Publisher Correction: Pancreatic duct ligation reduces premalignant pancreatic lesions in a Kras model of pancreatic adenocarcinoma in mice.(Nature Publishing Group, 2021-03-02) Cáceres, Marta; Quesada, Rita; Iglesias, Mar; Real Arribas, Francisco; Villamonte, Maria; de Villarreal, Jaime Martinez; Pérez, Mónica; Andaluz, Ana; Moll, Xavier; Berjano, Enrique; Dorcaratto, Dimitri; Sánchez-Velázquez, Patricia; Grande, LuÃs; BurdÃo, FernandoPublication A faecal microbiota signature with high specificity for pancreatic cancer.(BMJ Publishing Group, 2022-03-08) Kartal, Ece; Schmidt, Thomas S B; Wirbel, Jakob; Maistrenko, Oleksandr M; Akanni, Wasiu A; Alashkar Alhamwe, Bilal; Alves, Renato J; Carrato, Alfredo; Erasmus, Hans-Peter; Estudillo, Lidia; Finkelmeier, Fabian; Fullam, Anthony; Glazek, Anna M; Gómez-Rubio, Paulina; Hercog, Rajna; Jung, Ferris; Kandels, Stefanie; Kersting, Stephan; Langheinrich, Melanie; Márquez, Mirari; Molero, Xavier; Orakov, Askarbek; Van Rossum, Thea; Raul, Torres-Ruiz; Telzerow, Anja; Zych, Konrad; Benes, Vladimir; Zeller, Georg; Trebicka, Jonel; Bork, Peer; Malats, Nuria; Molina-Montes, Esther; Rodriguez Perales, Sandra; Real Arribas, Francisco; World Cancer Research Fund International; Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea; Federal Ministry of Education & Research (Alemania); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Instituto de Salud Carlos III; Red Temática de Investigación Cooperativa en Cáncer (RTICC) (España)Recent evidence suggests a role for the microbiome in pancreatic ductal adenocarcinoma (PDAC) aetiology and progression. To explore the faecal and salivary microbiota as potential diagnostic biomarkers. We applied shotgun metagenomic and 16S rRNA amplicon sequencing to samples from a Spanish case-control study (n=136), including 57 cases, 50 controls, and 29 patients with chronic pancreatitis in the discovery phase, and from a German case-control study (n=76), in the validation phase. Faecal metagenomic classifiers performed much better than saliva-based classifiers and identified patients with PDAC with an accuracy of up to 0.84 area under the receiver operating characteristic curve (AUROC) based on a set of 27 microbial species, with consistent accuracy across early and late disease stages. Performance further improved to up to 0.94 AUROC when we combined our microbiome-based predictions with serum levels of carbohydrate antigen (CA) 19-9, the only current non-invasive, Food and Drug Administration approved, low specificity PDAC diagnostic biomarker. Furthermore, a microbiota-based classification model confined to PDAC-enriched species was highly disease-specific when validated against 25 publicly available metagenomic study populations for various health conditions (n=5792). Both microbiome-based models had a high prediction accuracy on a German validation population (n=76). Several faecal PDAC marker species were detectable in pancreatic tumour and non-tumour tissue using 16S rRNA sequencing and fluorescence in situ hybridisation. Taken together, our results indicate that non-invasive, robust and specific faecal microbiota-based screening for the early detection of PDAC is feasible.Publication A Consensus Molecular Classification of Muscle-invasive Bladder Cancer.(Elsevier, 2020-04) Kamoun, Aurélie; de Reyniès, Aurélien; Allory, Yves; Sjödahl, Gottfrid; Robertson, A Gordon; Seiler, Roland; Hoadley, Katherine A; Groeneveld, Clarice S; Al-Ahmadie, Hikmat; Choi, Woonyoung; Castro, Mauro A A; Fontugne, Jacqueline; Eriksson, Pontus; Mo, Qianxing; Kardos, Jordan; Zlotta, Alexandre; Hartmann, Arndt; Dinney, Colin P; Bellmunt, Joaquim; Powles, Thomas; Malats, Núria; Chan, Keith S; Kim, William Y; McConkey, David J; Black, Peter C; Dyrskjøt, Lars; Höglund, Mattias; Lerner, Seth P; Real Arribas, Francisco; Radvanyi, François; Swedish Cancer Society (Cancerfonden); Lund Medical Faculty (ALF)BACKGROUND Muscle-invasive bladder cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, but the diversity of their subtype sets impedes their clinical application. OBJECTIVE To achieve an international consensus on MIBC molecular subtypes that reconciles the published classification schemes. DESIGN, SETTING, AND PARTICIPANTS We used 1750 MIBC transcriptomic profiles from 16 published datasets and two additional cohorts. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We performed a network-based analysis of six independent MIBC classification systems to identify a consensus set of molecular classes. Association with survival was assessed using multivariable Cox models. RESULTS AND LIMITATIONS We report the results of an international effort to reach a consensus on MIBC molecular subtypes. We identified a consensus set of six molecular classes: luminal papillary (24%), luminal nonspecified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics, including outcomes. We provide a single-sample classifier that assigns a consensus class label to a tumor sample's transcriptome. Limitations of the work are retrospective clinical data collection and a lack of complete information regarding patient treatment. CONCLUSIONS This consensus system offers a robust framework that will enable testing and validation of predictive biomarkers in future prospective clinical trials. PATIENT SUMMARY Bladder cancers are heterogeneous at the molecular level, and scientists have proposed several classifications into sets of molecular classes. While these classifications may be useful to stratify patients for prognosis or response to treatment, a consensus classification would facilitate the clinical use of molecular classes. Conducted by multidisciplinary expert teams in the field, this study proposes such a consensus and provides a tool for applying the consensus classification in the clinical setting.Publication Immunohistochemistry-Based Taxonomical Classification of Bladder Cancer Predicts Response to Neoadjuvant Chemotherapy.(Multidisciplinary Digital Publishing Institute (MDPI), 2020-07-03) Font, Albert; Domènech, Montserrat; BenÃtez, Raquel; Rava, Marta; Marqués, Miriam; RamÃrez, Jose L; Pineda, Silvia; DomÃnguez-RodrÃguez, Sara; Gago, José L; Badal, Josep; Carrato, Cristina; López, Héctor; Quer, Ariadna; Castellano, Daniel; Malats, Nuria; Real Arribas, Francisco; Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Unión EuropeaPlatinum-based neoadjuvant chemotherapy (NAC) increases the survival of patients with organ-confined urothelial bladder cancer (UBC). In retrospective studies, patients with basal/squamous (BASQ)-like tumors present with more advanced disease and have worse prognosis. Transcriptomics-defined tumor subtypes are associated with response to NAC. To investigate whether immunohistochemical (IHC) subtyping predicts NAC response. Patients with muscle-invasive UBC having received platinum-based NAC were identified. Tissue microarrays were used to type tumors for KRT5/6, KRT14, GATA3, and FOXA1. progression-free survival and disease-specific survival; univariable and multivariate Cox regression models were applied. We found a very high concordance between mRNA and protein expression. Using IHC-based hierarchical clustering, we classified 126 tumors in three subgroups: BASQ-like (FOXA1/GATA3 low; KRT5/6/14 high), Luminal-like (FOXA1/GATA3 high; KRT5/6/14 low), and mixed-cluster (FOXA1/GATA3 high; KRT5/6 high; KRT14 low). Applying multivariable analyses, patients with BASQ-like tumors were more likely to achieve a pathological response to NAC (OR 3.96; p = 0.017). The clinical benefit appeared reflected in the lack of significant survival differences between patients with BASQ-like and luminal tumors. Patients with BASQ-like tumors-identified through simple and robust IHC-have a higher likelihood of undergoing a pathological complete response to NAC. Prospective validation is required.Publication HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer.(EMBO Press, 2020-05-04) Kalisz, Mark; Bernardo, Edgar; Beucher, Anthony; Maestro, Miguel Angel; Del Pozo, Natalia; Millán, Irene; Haeberle, Lena; Schlensog, Martin; Safi, Sami Alexander; Knoefel, Wolfram Trudo; Grau, Vanessa; de Vas, MatÃas; Shpargel, Karl B; Vaquero, Eva; Magnuson, Terry; Ortega Jimenez, Sagrario; Esposito, Irene; Real Arribas, Francisco; Ferrer, Jorge; Wellcome Trust; UK Research and Innovation; Medical Research Council (Reino Unido); Unión Europea. Comisión Europea. European Research Council (ERC); Instituto de Salud Carlos III; Juvenile Diabetes Research Foundation; Fundación La Caixa; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España); NIHR - Imperial Biomedical Research Centre (Reino Unido)Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding Lysine-specific demethylase 6A, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutant transcriptomes phenocopy those of Kdm6a mutations, and both defects synergize with KrasG12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic, and biochemical studies to show that HNF1A recruits KDM6A to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates differentiated acinar cell programs, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. We also identify a subset of non-classical PDAC samples that exhibit the HNF1A/KDM6A-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A deficiency promotes PDAC. They also connect the tumor-suppressive role of KDM6A deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition.