We focus on the molecular pathophysiology of pancreatic ductal adenocarcinoma (PDAC) and urothelial carcinoma (UC), with a disease-oriented approach. We use patient samples, cultured cells, and genetically modified mice, giving a similar weight to the 3 model systems. Observations made at either of these levels are then extended through additional work. To translate the findings, we bring this knowledge to a ‘population’ level leveraging on information and samples from large patient cohorts.
In PDAC, a main hypothesis is that cell differentiation is a potent tumour suppressor mechanism acting early in carcinogenesis. We use the excellent genetic mouse models available because these processes cannot be readily studied in humans. In mice, PDAC can originate in pancreatic progenitors and in adult acinar and ductal cells. Understanding the contribution of early molecular events is crucial to design better strategies for early tumour detection and prevention in subjects at risk.
In UC, we focus on identifying new genes, using them for improved tumour taxonomy, characterising the mechanisms of action, and applying this knowledge for improved prediction of outcome and therapy.
Publications
Huang L, Jansen L, Balavarca Y, Molina-Montes E, Babaei M, van der Geest L, Lemmens V, Van Eycken L, De Schutter H, Johannesen TB, Fristrup CW, Mortensen MB, Žakelj MP, Zadnik V, Becker N, Hackert T, Magi M, Cassetti T, Sassatelli R, Grützmann R, Merkel S, Gonçalves AF, Bento MJ, Hegyi P, Lakatos G, Szentesi A, Moreau M, van de Velde T, Broeks A, Real FX, Carrato A, Molero X, Besselink MG, Malats N, Büchler MW, Schrotz-King P, Brenner H (2019).Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations. Gut 68, 130-139. CNIO Publication.
Rubio R, Martínez-Fernández M, Segovia C, Lodewijk I, Suarez C, Segrelles C, López-Calderón F, Munera-Maravilla E, Santos M, Garcia-Escudero R, Lorz C, Gomez-Rodriguez MJ, de Velasco G, Otero Blas I, Villacampa F, Ruiz S, de la Rosa F, Domínguez-Rodríguez S, Real FX, Malats N, Castellano D, Dueñas M, Paramio J (2019).Cdk4/6-inhibition induces bladder cancer regression independently of RB1 gene status. Clin Cancer Res 25, 390-402. CNIO Publication.
Kamoun A, Reyniès A, Allory Y, Sjödahl G, Gordon Robertson A, Seiler R, Hoadley KA, Groeneveld CS, Al-Ahmadie H, Choi W, Castro MAA, Fontugne J, Eriksson P, Mo Q, Kardos J, Zlotta A, Hartmann A, Dinney CP, Bellmunt J, Powles T, Malats N, Chan KS, Kim WY, McConkey DJ, Black PC, Dyrskjøt L, Höglund M, Lerner SP, Real FX, Radvanyi F; Bladder Cancer Molecular Taxonomy Group (2019).A Consensus Molecular Classification of Muscle-invasive Bladder Cancer. Eur Urol (in press). CNIO Publication.
Rubio C, Martínez-Fernández M, Segovia C, Lodewijk I, Suarez-Cabrera C, Segrelles C, López-Calderón F, Munera-Maravilla E, Santos M, Bernardini A, García-Escudero R, Lorz C, Gómez-Rodriguez MJ, de Velasco G, Otero I, Villacampa F, Guerrero-Ramos F, Ruiz S, de la Rosa F, Domínguez-Rodríguez S, Real FX, Malats N, Castellano D, Dueñas M, Paramio JM (2019).CDK4/6 Inhibitor as a Novel Therapeutic Approach for Advanced Bladder Cancer Independently of RB1 Status. Clin Cancer Res 25, 390-402. CNIO Publication.
Gomez-Rubio P, Piñero J, Molina-Montes E, Gutiérrez-Sacristán A, Marquez M, Rava M, Michalski CW, Farré A, Molero X, Löhr M, Perea J, Greenhalf W, O'Rorke M, Tardón A, Gress T, Barberá VM, Crnogorac-Jurcevic T, Muñoz-Bellvís L, Domínguez-Muñoz E, Balsells J, Costello E, Yu J, Iglesias M, Ilzarbe L, Kleeff J, Kong B, Mora J, Murray L, O'Driscoll D, Poves I, Lawlor RT, Ye W, Hidalgo M, Scarpa A, Sharp L, Carrato A, Real FX, Furlong LI, Malats N; PanGenEU Study Investigators (2019).Pancreatic cancer and autoimmune diseases: An association sustained by computational and epidemiological case-control approaches. Int J Cancer 144, 1540-1549. CNIO Publication.
Cobo I, Martinelli P, Flández M, Bakiri L, Zhang M, Carrillo-de-Santa-Pau E, Jia J, Sánchez-Arévalo Lobo VJ, Megías D, Felipe I, Del Pozo N, Millán I, Thommesen L, Bruland T, Olson SH, Smith J, Schoonjans K, Bamlet WR, Petersen GM, Malats N, Amundadottir LT, Wagner EF, Real FX (2018).Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. Nature 554, 533-537. CNIO Publication.
Rubio C, Martínez-Fernández M, Segovia C, Lodewijk I, Suarez-Cabrera C, Segrelles C, López-Calderón F, Munera-Maravilla E, Santos M, Bernardini A, García-Escudero R, Lorz C, Gómez-Rodriguez MJ, de Velasco G, Otero I, Villacampa F, Guerrero-Ramos F, Ruiz S, de la Rosa F, Domínguez-Rodríguez S, Real FX, Malats N, Castellano D, Dueñas M, Paramio JM. (2018).CDK4/6 Inhibitor as a Novel Therapeutic Approach for Advanced Bladder Cancer Independently of RB1 Status.. Clin Cancer Res (in press). CNIO Publication.
Molina-Montes E, Gomez-Rubio P, Márquez M, Rava M, Löhr M, Michalski CW, Molero X, Farré A, Perea J, Greenhalf W, Ilzarbe L, O'Rorke M, Tardón A, Gress T, Barberà VM, Crnogorac-Jurcevic T, Domínguez-Muñoz E, Muñoz-Bellvís L, Balsells J, Costello E, Huang J, Iglesias M, Kleeff J, Kong B, Mora J, Murray L, O'Driscoll D, Poves I, Scarpa A, Ye W, Hidalgo M, Sharp L, Carrato A, Real FX, Malats N; PanGenEU Study Investigators (2018).Risk of pancreatic cancer associated with family history of cancer and other medical conditions by accounting for smoking among relatives. Int J Epidemiol 47, 473-483. CNIO Publication.
Villamayor L, Rodríguez-Seguel E, Araujo R, Carrasco M, Bru-Tarí E, Mellado-Gil JM, Gauthier BR, Martinelli P, Quesada I, Soria B, Martín F, Cano DA, Rojas A (2018).GATA6 Controls Insulin Biosynthesis and Secretion in Adult ß-Cells. Diabetes 67, 448-460. CNIO Publication.
Gómez-Rubio P, Zock JP, Rava M, Marquez M, Sharp L, Hidalgo M, Carrato A, Ilzarbe L, Michalski C, Molero X, Farré A, Perea J, Greenhalf W, O'Rorke M, Tardón A, Gress T, Barberà V, Crnogorac-Jurcevic T, Domínguez-Muñoz E, Muñoz-Bellvís L, Alvarez-Urturi C, Balcells J, Barneo L, Costello E, Guillén-Ponce C, Kleeff J, Kong B, Lawlor R, Löhr M, Mora J, Murray L, O'Driscoll D, Peláez P, Poves I, Scarpa A, Real FX, Malats N; PanGenEU Study Investigators (2017).Reduced risk of pancreatic cancer associated with asthma and nasal allergies.. Gut 66, 314-322. CNIO Publication.
Gomez-Rubio P, Rosato V, Marquez M, Bosetti C, Molina-Montes E, Rava M, Piñero J, Michalski CW, Farré A, Molero X, Löhr M, Ilzarbe L, Perea J, Greenhalf W, O'Rorke M, Tardón A, Gress T, Barberà VM, Crnogorac-Jurcevic T, Muñoz-Bellvís L, Domínguez-Muñoz E, Gutiérrez-Sacristán A, Balsells J, Costello E, Guillén-Ponce C, Huang J, Iglesias M, Kleeff J, Kong B, Mora J, Murray L, O'Driscoll D, Peláez P, Poves I, Lawlor RT, Carrato A, Hidalgo M, Scarpa A, Sharp L, Furlong LI, Real FX, La Vecchia C, Malats N; PanGenEU Study Investigators. (2017).A systems approach identifies time-dependent associations of multimorbidities with pancreatic cancer risk.. Ann Oncol 28, 1618-1624. CNIO Publication.
Notta F, Chan-Seng-Yue M, Lemire M, Li Y, Wilson GW, Connor AA, Denroche RE, Liang SB, Brown AM, Kim JC, Wang T, Simpson JT, Beck T, Borgida A, Buchner N, Chadwick D, Hafezi-Bakhtiari S, Dick JE, Heisler L, Hollingsworth MA, Ibrahimov E, Jang GH, Johns J, Jorgensen LG, Law C, Ludkovski O, Lungu I, Ng K, Pasternack D, Petersen GM, Shlush LI, Timms L, Tsao MS, Wilson JM, Yung CK, Zogopoulos G, Bartlett JM, Alexandrov LB, Real FX, Cleary SP, Roehrl MH, McPherson JD, Stein LD, Hudson TJ, Campbell PJ, Gallinger S (2016).A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns.. Nature 538, 378-382. CNIO Publication.
Zhou W, Machiela MJ, Freedman ND, Rothman N, Malats N, Dagnall C, Caporaso N, Teras LT, Gaudet MM, Gapstur SM, Stevens VL, Jacobs KB, Sampson J, Albanes D, Weinstein S, Virtamo J, Berndt S, Hoover RN, Black A, Silverman D, Figueroa J, Garcia-Closas M, Real FX, Earl J, Marenne G, Rodriguez-Santiago B, Karagas M, Johnson A, Schwenn M, Wu X, Gu J, Ye Y, Hutchinson A, Tucker M, Perez-Jurado LA, Dean M, Yeager M, Chanock SJ (2016).Mosaic loss of chromosome Y is associated with common variation near TCL1A.. Nat Genet 48, 563-568. CNIO Publication.
Hedegaard J, Lamy P, Nordentoft I, Algaba F, Høyer S, Ulhøi BP, Vang S, Reinert T, Hermann GG, Mogensen K, Thomsen MB, Nielsen MM, Marquez M, Segersten U, Aine M, Höglund M, Birkenkamp-Demtröder K, Fristrup N, Borre M, Hartmann A, Stöhr R, Wach S, Keck B, Seitz AK, Nawroth R, Maurer T, Tulic C, Simic T, Junker K, Horstmann M, Harving N, Petersen AC, Calle ML, Steyerberg EW, Beukers W, van Kessel KE, Jensen JB, Pedersen JS, Malmström PU, Malats N, Real FX, Zwarthoff EC, Ørntoft TF, Dyrskjøt L (2016).Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma.. Cancer Cell 30, 27-42. CNIO Publication.
Machiela MJ, Zhou W, Karlins E, Sampson JN, Freedman ND, Yang Q, Hicks B, Dagnall C, Hautman C, Jacobs KB, Abnet CC, Aldrich MC, Amos C, Amundadottir LT, Arslan AA, Beane-Freeman LE, Berndt SI, Black A, Blot WJ, Bock CH, Bracci PM, Brinton LA, Bueno-de-Mesquita HB, Burdett L, Buring JE, Butler MA, Canzian F, Carreón T, Chaffee KG, Chang IS, Chatterjee N, Chen C, Chen C, Chen K, Chung CC, Cook LS, Crous Bou M, Cullen M, Davis FG, De Vivo I, Ding T, Doherty J, Duell EJ, Epstein CG, Fan JH, Figueroa JD, Fraumeni JF, Friedenreich CM, Fuchs CS, Gallinger S, Gao YT, Gapstur SM, Garcia-Closas M, Gaudet MM, Gaziano JM, Giles GG, Gillanders EM, Giovannucci EL, Goldin L, Goldstein AM, Haiman CA, Hallmans G, Hankinson SE, Harris CC, Henriksson R, Holly EA, Hong YC, Hoover RN, Hsiung CA, Hu N, Hu W, Hunter DJ, Hutchinson A, Jenab M, Johansen C, Khaw KT, Kim HN, Kim YH, Kim YT, Klein AP, Klein R, Koh WP, Kolonel LN, Kooperberg C, Kraft P, Krogh V, Kurtz RC, LaCroix A, Lan Q, Landi MT, Marchand LL, Li D, Liang X, Liao LM, Lin D, Liu J, Lissowska J, Lu L, Magliocco AM, Malats N, Matsuo K, McNeill LH, McWilliams RR, Melin BS, Mirabello L, Moore L, Olson SH, Orlow I, Park JY, Patiño-Garcia A, Peplonska B, Peters U, Petersen GM, Pooler L, Prescott J, Prokunina-Olsson L, Purdue MP, Qiao YL, Rajaraman P, Real FX, Riboli E, Risch HA, Rodriguez-Santiago B, Ruder AM, Savage SA, Schumacher F, Schwartz AG, Schwartz KL, Seow A, Wendy Setiawan V, Severi G, Shen H, Sheng X, Shin MH, Shu XO, Silverman DT, Spitz MR, Stevens VL, Stolzenberg-Solomon R, Stram D, Tang ZZ, Taylor PR, Teras LR, Tobias GS, Van Den Berg D, Visvanathan K, Wacholder S, Wang JC, Wang Z, Wentzensen N, Wheeler W, White E, Wiencke JK, Wolpin BM, Wong MP, Wu C, Wu T, Wu X, Wu YL, Wunder JS, Xia L, Yang HP, Yang PC, Yu K, Zanetti KA, Zeleniuch-Jacquotte A, Zheng W, Zhou B, Ziegler RG, Perez-Jurado LA, Caporaso NE, Rothman N, Tucker M, Dean MC, Yeager M, Chanock SJ (2016).Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome. Nat Commun 7, 11843. CNIO Publication. Open Access
Toll A, Fernández LC, Pons T, Groesser L, Sagrera A, Carrillo-de Santa Pau E, Vicente A, Baselga E, Vázquez M, Beltrán S, Pisano DG, Rueda D, Gut M, Pujol RM, Hafner C, Gut I, Valencia A, Real FX (2016).Somatic embryonic FGFR2 mutations in keratinocytic epidermal nevi.. J Invest Dermatol 136, 1718-1721. CNIO Publication.
Maraver A, Fernandez-Marcos PJ, Cash TP, Mendez-Pertuz M, Dueñas M, Maietta P, Martinelli P, Muñoz-Martin M, Martínez-Fernández M, Cañamero M, Roncador G, Martinez-Torrecuadrada JL, Grivas D, de la Pompa JL, Valencia A, Paramio JM, Real FX, Serrano M (2015).NOTCH pathway inactivation promotes bladder cancer progression.. J Clin Invest 125, 824-830. CNIO Publication.
Figueroa JD, Koutros S, Colt JS, Kogevinas M, Garcia-Closas M, Real FX, Friesen MC, Baris D, Stewart P, Schwenn M, Johnson A, Karagas MR, Armenti KR, Moore LE, Schned A, Lenz P, Prokunina-Olsson L, Banday AR, Paquin A, Ylaya K, Chung JY, Hewitt SM, Nickerson ML, Tardón A, Serra C, Carrato A, García-Closas R, Lloreta J, Malats N, Fraumeni JF Jr, Chanock SJ, Chatterjee N, Rothman N, Silverman DT (2015).Modification of Occupational Exposures on Bladder Cancer Risk by Common Genetic Polymorphisms.. J Natl Cancer I 107, djv223. CNIO Publication.
Machiela MJ, Zhou W, Sampson JN, Dean MC, Jacobs KB, Black A, Brinton LA, Chang IS, Chen C, Chen C, Chen K, Cook LS, Crous Bou M, De Vivo I, Doherty J, Friedenreich CM, Gaudet MM, Haiman CA, Hankinson SE, Hartge P, Henderson BE, Hong YC, Hosgood HD 3rd, Hsiung CA, Hu W, Hunter DJ, Jessop L, Kim HN, Kim YH, Kim YT, Klein R, Kraft P, Lan Q, Lin D, Liu J, Le Marchand L, Liang X, Lissowska J, Lu L, Magliocco AM, Matsuo K, Olson SH, Orlow I, Park JY, Pooler L, Prescott J, Rastogi R, Risch HA, Schumacher F, Seow A, Setiawan VW, Shen H, Sheng X, Shin MH, Shu XO, VanDen Berg D, Wang JC, Wentzensen N, Wong MP, Wu C, Wu T, Wu YL, Xia L, Yang HP, Yang PC, Zheng W, Zhou B, Abnet CC, Albanes D, Aldrich MC, Amos C, Amundadottir LT, Berndt SI, Blot WJ, Bock CH, Bracci PM, Burdett L, Buring JE, Butler MA, Carreón T, Chatterjee N, Chung CC, Cook MB, Cullen M, Davis FG, Ding T, Duell EJ, Epstein CG, Fan JH, Figueroa JD, Fraumeni JF Jr, Freedman ND, Fuchs CS, Gao YT, Gapstur SM, Patiño-Garcia A, Garcia-Closas M, Gaziano JM, Giles GG, Gillanders EM, Giovannucci EL, Goldin L, Goldstein AM, Greene MH, Hallmans G, Harris CC, Henriksson R, Holly EA, Hoover RN, Hu N, Hutchinson A, Jenab M, Johansen C, Khaw KT, Koh WP, Kolonel LN, Kooperberg C, Krogh V, Kurtz RC, LaCroix A, Landgren A, Landi MT, Li D, Liao LM, Malats N, McGlynn KA, McNeill LH, McWilliams RR, Melin BS, Mirabello L, Peplonska B, Peters U, Petersen GM, Prokunina-Olsson L, Purdue M, Qiao YL, Rabe KG, Rajaraman P, Real FX, Riboli E, Rodríguez-Santiago B, Rothman N, Ruder AM, Savage SA, Schwartz AG, Schwartz KL, Sesso HD, Severi G, Silverman DT, Spitz MR, Stevens VL, Stolzenberg-Solomon R, Stram D, Tang ZZ, Taylor PR, Teras LR, Tobias GS, Viswanathan K, Wacholder S, Wang Z, Weinstein SJ, Wheeler W, White E, Wiencke JK, Wolpin BM, Wu X, Wunder JS, Yu K, Zanetti KA, Zeleniuch-Jacquotte A, Ziegler RG, de Andrade M, Barnes KC, Beaty TH, Bierut LJ, Desch KC, Doheny KF, Feenstra B, Ginsburg D, Heit JA, Kang JH, Laurie CA, Li JZ, Lowe WL, Marazita ML, Melbye M, Mirel DB, Murray JC, Nelson SC, Pasquale LR, Rice K, Wiggs JL, Wise A, Tucker M, Pérez-Jurado LA, Laurie CC, Caporaso NE, Yeager M, Chanock SJ. (2015).Characterization of large structural genetic mosaicism in human autosomes.. Am J Hum Genet 96, 487-497. CNIO Publication.
Mocci E, Guillen-Ponce C, Earl J, Marquez M, Solera J, Salazar-López MT, Calcedo-Arnáiz C, Vázquez-Sequeiros E, Montans J, Muñoz-Beltrán M, Vicente-Bártulos A, González-Gordaliza C, Sanjuanbenito A, Guerrero C, Mendía E, Lisa E, Lobo E, Martínez JC, Real FX, Malats N, Carrato A. (2015).PanGen-Fam: Spanish registry of hereditary pancreatic cancer.. Eur J Cancer 51, 1911-1917. CNIO Publication.
Derikx MH, Kovacs P, Scholz M, Masson E, Chen JM, Ruffert C, Lichtner P, Te Morsche RH, Cavestro GM; PanEuropean Working group on Alcoholic Chronic Pancreatitis members and collaborators, Férec C, Drenth JP, Witt H, Rosendahl J, Algül H, Berg T, Bödeker H, Blüher M, Bruno MJ, Buch S, Bugert P, Cichoz-Lach H, Dabrowski A, Farré A, Frank J, Gasiorowska A, Geisz A, Goni E, Grothaus J, Grützmann R, Haas S, Hampe J, Hellerbrand C, Hegyi P, Huster D, Ioana M, Iordache S, Jurkowska G, Keim V, Landt O, Di Leo M, Lerch MM, Lévy P, Löhr MJ, Macek M, Malats N, Malecka-Panas E, Mariani A, Martorana D, Mayerle J, Mora J, Mössner J, Müller S, Ockenga J, Paderova J, Pedrazzoli S, Pereira SP, Pfützer R, Real FX, Rebours V, Ridinger M, Rietschel M, Rohde K, Sack S, Saftoiu A, Schneider A, Schulz HU, Soyka M, Simon P, Skipworth J, Stickel F, Stumvoll M, Testoni PA, Tönjes A, Treiber M, Weiss FU, Werner J, Wodarz N (2014).Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study.. Gut (in press). CNIO Publication.
Martín-Sánchez E, Odqvist L, Rodríguez-Pinilla SM, Sánchez-Beato M, Roncador G, Domínguez-González B, Blanco-Aparicio C, García Collazo AM, Cantalapiedra EG, Fernández JP, Curiel del Olmo S, Pisonero H, Madureira R, Almaraz C, Mollejo M, Alves FJ, Menárguez J, González-Palacios F, Rodríguez-Peralto JL, Ortiz-Romero PL, Real FX, García JF, Bischoff JR, Piris MA (2014).PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases.. PLoS ONE 9, e1121148. CNIO Publication.
Pineda S, Milne RL, Calle ML, Rothman N, López de Maturana E, Herranz J, Kogevinas M, Chanock SJ, Tardón A, Márquez M, Guey LT, García-Closas M, Lloreta J, Baum E, González-Neira A, Carrato A, Navarro A, Silverman DT, Real FX, Malats N (2014).Genetic Variation in the TP53 Pathway and Bladder Cancer Risk. A Comprehensive Analysis.. PLoS ONE 9, e89952.. CNIO Publication.
López de Maturana E, Chanok SJ, Picornell AC, Rothman N, Herranz J, Calle ML, García-Closas M, Marenne G, Brand A, Tardón A, Carrato A, Silverman DT, Kogevinas M, Gianola D, Real FX, Malats N (2014).Whole Genome Prediction of Bladder Cancer Risk With the Bayesian LASSO.. Genet Epidemiol 38, 467-476. CNIO Publication.