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 Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts(eLife Sciences Publications, 2017) van der Lelij, Petra; Lieb, Simone; Jude, Julian; Wutz, Gordana; Santos, Catarina P; Falkenberg, Katrina; Schlattl, Andreas; Ban, Jozef; Schwentner, Raphaela; Hoffmann, Thomas; Kovar, Heinrich; Real Arribas, Francisco; Waldman, Todd; Pearson, Mark A; Kraut, Norbert; Peters, Jan-Michael; Zuber, Johannes; Petronczki, Mark; FWF Austrian Science Fund; Austrian Research Promotion Agency; Unión Europea. Comisión Europea. European Research Council (ERC); Asociación Española Contra el Cáncer; National Institutes of Health (Estados Unidos)Recent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 support sister chromatid cohesion to redundantly ensure cell survival. STAG1 represents a vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2 across different cancer contexts. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics.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 Genetic variation in the TP53 pathway and bladder cancer risk. a comprehensive analysis.(Public Library of Science (PLOS), 2014-05-12) Pineda, Silvia; Milne, Roger L; Calle, M Luz; Rothman, Nathaniel; Herranz, Jesús; Kogevinas, Manolis; Chanock, Stephen J; Tardón, Adonina; Márquez, Mirari; Guey, Lin T; GarcÃa-Closas, Montserrat; Lloreta, Josep; Baum, Erin; Carrato, Alfredo; Navarro, Arcadi; Silverman, Debra T; Lopez de Maturana, Evangelina; Malats, Nuria; Gonzalez Neira, Anna; Real Arribas, Francisco; Instituto de Salud Carlos III; Red Temática de Investigación Cooperativa en Cáncer (RTICC) (España); Fundación La Marató TV3; Unión Europea; United States Department of Health and Human Services; Institució Catalana de Recerca i Estudis AvançatsGermline variants in TP63 have been consistently associated with several tumors, including bladder cancer, indicating the importance of TP53 pathway in cancer genetic susceptibility. However, variants in other related genes, including TP53 rs1042522 (Arg72Pro), still present controversial results. We carried out an in depth assessment of associations between common germline variants in the TP53 pathway and bladder cancer risk. We investigated 184 tagSNPs from 18 genes in 1,058 cases and 1,138 controls from the Spanish Bladder Cancer/EPICURO Study. Cases were newly-diagnosed bladder cancer patients during 1998-2001. Hospital controls were age-gender, and area matched to cases. SNPs were genotyped in blood DNA using Illumina Golden Gate and TaqMan assays. Cases were subphenotyped according to stage/grade and tumor p53 expression. We applied classical tests to assess individual SNP associations and the Least Absolute Shrinkage and Selection Operator (LASSO)-penalized logistic regression analysis to assess multiple SNPs simultaneously. Based on classical analyses, SNPs in BAK1 (1), IGF1R (5), P53AIP1 (1), PMAIP1 (2), SERINPB5 (3), TP63 (3), and TP73 (1) showed significant associations at p-value≤0.05. However, no evidence of association, either with overall risk or with specific disease subtypes, was observed after correction for multiple testing (p-value≥0.8). LASSO selected the SNP rs6567355 in SERPINB5 with 83% of reproducibility. This SNP provided an OR = 1.21, 95%CI 1.05-1.38, p-value = 0.006, and a corrected p-value = 0.5 when controlling for over-estimation. We found no strong evidence that common variants in the TP53 pathway are associated with bladder cancer susceptibility. Our study suggests that it is unlikely that TP53 Arg72Pro is implicated in the UCB in white Europeans. SERPINB5 and TP63 variation deserve further exploration in extended studies.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 Reply to 'Mosaic loss of chromosome Y in leukocytes matters'.(Nature Publishing Group, 2019-01) Zhou, Weiyin; Machiela, Mitchell J; Freedman, Neal D; Rothman, Nathaniel; Malats, Nuria; Dagnall, Casey; Caporaso, Neil; Teras, Lauren T; Gaudet, Mia M; Gapstur, Susan M; Stevens, Victoria L; Jacobs, Kevin B; Sampson, Joshua; Albanes, Demetrius; Weinstein, Stephanie; Virtamo, Jarmo; Berndt, Sonja; Hoover, Robert N; Black, Amanda; Silverman, Debra; Figueroa, Jonine; Garcia-Closas, Montserrat; Real Arribas, Francisco; Earl, Julie; Marenne, Gaelle; Rodriguez-Santiago, Benjamin; Karagas, Margaret; Johnson, Alison; Schwenn, Molly; Wu, Xifeng; Gu, Jian; Ye, Yuanqing; Hutchinson, Amy; Tucker, Margaret; Perez-Jurado, Luis A; Dean, Michael; Yeager, Meredith; Chanock, Stephen J; United States Department of Health and Human ServicesPublication 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.