Epithelial Carcinogenesis Group

Francisco X. Real Group Leader
T +34 917328000 (Ext 3660)
freal@cnio.es

Research Scientists

Miriam Marqués

Post-Doctoral Fellows

Michele Bevere
Mikhail Chesnokov
Alejandro Da Silva
Irene Felipe
Eleonora Lapi
Jaime Martínez de Villarreal

Graduate Students

Shidong Deng
Sarah Klauß
Issis Abril Pérez
Chengsi Wu

Technicians

Ruth Josefina Micha
Leticia Rodríguez

Visiting Scientist

Fernando Burdío
Luis César Fernández
Mark Kalisz
Gabriel Piedrafita

We focus on the molecular pathophysiology of pancreatic ductal adenocarcinoma (PDAC) and bladder carcinoma, taking a disease-oriented approach. These tumours present very distinct challenges. We learn from patient samples, cultured cells/organoids, and genetically modified mice. To translate the findings, we bring this knowledge to a ‘population’ level — leveraging on information and samples from large patient cohorts — together with Núria Malats (CNIO).

PDAC has a dismal prognosis even when diagnosed early. We aim at dissecting the molecular mechanisms involved in the very early steps of tumour development. We harness the power of genetic mouse models to answer questions that cannot be tackled in humans. We hypothesise that cell differentiation is an early, potent, tumour suppressor mechanism. Identifying early molecular events is crucial to design better strategies for prevention and early tumour detection.

Bladder cancer is a very heterogeneous tumour, presenting a wide range of clinical problems. We aim at acquiring knowledge of the underlying biology and genetics that might impact tumour subclassification, outcome prediction, and therapy selection.

Recent publications

Cervilla S, Grases D, Perez E, Real FX, Musulen E, Aprea J, Esteller M, Porta-Pardo E. (2026). A technical comparison of spatial transcriptomics platforms across six cancer types. Genome Biol (in press). CNIO Publication.
Prip F, Lamy P, Lindskrog SV, Strandgaard T, Nordentoft I, Birkenkamp-Demtröder K, Birkbak NJ, Kristjánsdóttir N, Kjær A, Andreasen TG, Ahrenfeldt J, Pedersen JS, Rasmussen AM, Hermann GG, Mogensen K, Petersen AC, Hartmann A, Grimm MO, Horstmann M, Nawroth R, Segersten U, Sikic D, van Kessel KEM, Zwarthoff EC, Maurer T, Simic T, Malmström PU, Malats N, Jensen JB; UROMOL Consortium; Real FX, Dyrskjøt L (2025). Allelic effects on KLHL17 expression underlie a pancreatic cancer genome-wide association signal at chr1p36.33. Nat Genet 16, 4055. CNIO Publication.
Bodas C, Felipe I, Chanez B, Lafarga M, Lopez de Maturana E, Martinez de Villarreal J, Del Pozo N, Malumbres M, Vargiu P, Cayuela A, Peset I, Connelly K, Hoskins J, Méndez R, Amundadottir L, Malats N, Ortega S, Real FX. (2025). A Common CTRB misfolding variant associated with pancreatic cancer risk causes ER stress and inflammation in mice. Gut 74, 1452-1466. CNIO Publication.
Felipe I, Kalisz M. (2025). Distinct gene expression mechanisms in classical and basal PDAC subtypes. Gut 75, 1-2. CNIO Publication.
Hergueta-Redondo M, Sánchez-Redondo S, Hurtado B, Santos V, Pérez-Martínez M, Ximénez-Embún P, McDowell SAC, Mazariegos MS, Mata G, Torres-Ruiz R, Rodríguez-Perales S, Martínez L, Graña-Castro O, Megias D, Quail D, Quintela-Fandino M, Peinado H. (2025). The impact of a high fat diet and platelet activation on pre-metastatic niche formation. Nat Commun 16, 2897. CNIO Publication.
Sevilla-Ortega C, Angelina A, Martín-Cruz L, Pérez-Diego M, Maldonado A, Lavín B, Marcos-Ramiro B, Pérez de Llano L, Gayá A, Real FX, Conejero L, Subiza JL, Palomares O. (2025). A mucosal vaccine prevents eosinophilic allergic airway inflammation by modulating immune responses to allergens in a murine model of airway disease. Nat Commun 16, 7129. CNIO Publication.
Villoslada-Blanco P, Alonso L, Sabroso-Lasa S, Maquedano M, Estudillo L, Real FX, López de Maturana E, Malats N (2025). Development of a consensus molecular classifier for pancreatic ductal adenocarcinoma. Genome Med 17, 142. CNIO Publication.
Coolens K, Van der Vliet M, Van Campenhout J, del Pozo N, Torres-Cano A, Olson C, Xu J, Lickert H, Rovira,M, Houbracken I, Baldan J, Real FX, Spagnoli F, Rooman I (2025). ΔNP63 Defines an Exocrine-committed Subset of Murine Pancreatic Progenitor Cells. Cell Mol Gastroenterol Hepatol 20, 101715. CNIO Publication.
Sibai M, Cervilla S, Grases D, Musulen E, Lazcano R, Mo CK, Davalos V, Fortian A, Bernat A, Romeo M, Tokheim C, Barretina J, Lazar AJ, Ding L; DUTRENEO Study Investigators; Grande E, Real FX, Esteller M, Bailey MH, Porta-Pardo E. (2025). The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity. Cell Reports 44, 115229. CNIO Publication.
Cañizo CG, Guerrero-Ramos F, Perez Escavy M, Lodewijk I, Suárez-Cabrera C, Morales L, Nunes SP, Munera-Maravilla E, Rubio C, Sánchez R, Rodriguez-Izquierdo M, Martínez de Villarreal J, Real FX, Castellano D, Martín-Arriscado C, Lora Pablos D, Rodríguez Antolín A, Dueñas M, Paramio JM, Martínez VG. (2025). Characterisation of the tumour microenvironment and PD-L1 granularity reveals the prognostic value of cancer-associated myofibroblasts in non-invasive bladder cancer. Oncoimmunology 14, 2438291. CNIO Publication.
He J, Alhamwe BA, Sabroso S, Carrato A, Hidalgo M, Molero X, Iglesias M, Perea J, Farré A, Tardón A, Dominguez-Muñoz E, Barberà V, Muñoz-Bellvís L, Löhr M, Greenhalf W, O'Rorke M, Gress T, Crnogorac-Jurcevic T, Gayà A, Langtry A, Kleeff J, Lawlor R, Real FX, Renz H, Malats N; PanGenEU Study Investigators. (2025). Low type-2 immune effectors modulate atopic diseases’ protective role in pancreatic cancer risk. Int J Cancer 157, 468-479. CNIO Publication.
Herms A, Fernandez-Antoran D, Alcolea MP, Kalogeropoulou A, Banerjee U, Piedrafita G, Abby E, Valverde-Lopez JA, Ferreira IS, Caseda I, Bejar MT, Dentro SC, Vidal-Notari S, Ong SH, Colom B, Murai K, King C, Mahbubani K, Saeb-Parsy K, Lowe AR, Gerstung M, Jones PH. (2024). Self-sustaining long-term 3D epithelioid cultures reveal drivers of clonal expansion in esophageal epithelium. Nat Genet 56, 2158-2173. CNIO Publication.
Ramal M, Corral S, Kalisz M, Lapi E, Real FX. (2024). The urothelial gene regulatory network: understanding biology to improve bladder cancer management. Oncogene 43, 1-21. CNIO Publication.
Bustamante-Madrid P, Barbáchano A, Albandea-Rodríguez D, Rodríguez-Cobos J, Rodríguez-Salas N, Prieto I, Burgos A, Martínez de Villarreal J, Real FX, González-Sancho JM, Larriba MJ, Lafarga M, Muñoz A, Fernández-Barral A. (2024). Vitamin D opposes multilineage cell differentiation induced by Notch inhibition and BMP4 pathway activation in human colon organoids. Cell Death Dis 15, 301. CNIO Publication.
Font A, Mellado B, Climent MA, Virizuela JA, Oudard S, Puente J, Castellano D, González-Del-Alba A, Pinto A, Morales-Barrera R, Rodriguez-Vida A, Fernandez PL, Teixido C, Jares P, Aldecoa I, Gibson N, Solca F, Mondal S, Lorence RM, Serra J, Real FX. (2024). Phase II trial of afatinib in patients with advanced urothelial carcinoma with genetic alterations in ERBB1-3 (LUX-Bladder 1). Br J Cancer 130, 434-441. CNIO Publication.
Felipe I, Real FX. (2024). PDAC heterogeneity resolved spatially at the single-cell level: new biological answers, new questions on optimal translation†. J Pathol 263, 397-399. CNIO Publication.
Abby E, Dentro SC, Hall MWJ, Fowler JC, Ong SH, Sood R, Herms A, Piedrafita G, Abnizova I, Siebel CW, Gerstung M, Hall BA, Jones PH. (2023). Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth. Nat Genet 55, 232-245. CNIO Publication.
de Andrés MP, Jackson RJ, Felipe I, Zagorac S, Pilarsky C, Schlitter AM, Martinez de Villareal J, Jang GH, Costello E, Gallinger S, Ghaneh P, Greenhalf W, Knösel T, Palmer DH, Ruemmele P, Weichert W, Buechler M, Hackert T, Neoptolemos JP, Notta F, Malats N, Martinelli P, Real FX. (2023). GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma. Gut 72, 535-548. CNIO Publication.
Cobo I, Paliwal S, Bodas C, Felipe I, Melià-Alomà J, Torres A, Martínez-Villarreal J, Malumbres M, García F, Millán I, Del Pozo N, Park JC, MacDonald RJ, Muñoz J, Méndez R, Real FX. (2023). NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation. Nat Commun 14, 3761. CNIO Publication.
de Villarreal JM, Kalisz M, Piedrafita G, Graña-Castro O, Chondronasiou D, Serrano M, Real FX. (2023). Pseudoalignment tools as an efficient alternative to detect repeated transposable elements in scRNAseq data. Bioinformatics 39, btac737. CNIO Publication.
Marqués M, Corral S, Sánchez-Díaz M, Del Pozo N, Martínez de Villarreal J, Schweifer N, Zagorac I, Hilberg F, Real FX. (2023). Tumor and Stromal Cell Targeting with Nintedanib and Alpelisib Overcomes Intrinsic Bladder Cancer Resistance. Mol Cancer Ther 22, 616-629. CNIO Publication.
King SD, Veliginti S, Brouwers MCGJ, Ren Z, Zheng W, Setiawan VW, Wilkens LR, Shu XO, Arslan AA, Beane Freeman LE, Bracci PM, Canzian F, Du M, Gallinger SJ, Giles GG, Goodman PJ, Haiman CA, Kogevinas M, Kooperberg C, LeMarchand L, Neale RE, Visvanathan K, White E, Albanes D, Andreotti G, Babic A, Berndt SI, Brais LK, Brennan P, Buring JE, Rabe KG, Bamlet WR, Chanock SJ, Fuchs CS, Gaziano JM, Giovannucci EL, Hackert T, Hassan MM, Katzke V, Kurtz RC, Lee IM, Malats N, Murphy N, Oberg AL, Orlow I, Porta M, Real FX, Rothman N, Sesso HD, Silverman DT, Thompson IM, Wactawski-Wende J, Wang X, Wentzensen N, Yu H, Zeleniuch-Jacquotte A, Yu K, Wolpin BM, Duell EJ, Li D, Hung RJ, Perdomo S, McCullough ML, Freedman ND, Patel AV, Peters U, Riboli E, Sund M, Tjønneland A, Zhong J, Van Den Eeden SK, Kraft P, Risch HA, Amundadottir LT, Klein AP, Stolzenberg-Solomon RZ, Antwi SO. (2023). Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization. Cancer Epidem Biomar 32, 1265-1269. CNIO Publication.
Rao N, Starrett GJ, Piaskowski ML, Butler KE, Golubeva Y, Yan W, Lawrence SM, Dean M, Garcia-Closas M, Baris D, Johnson A, Schwenn M, Malats N, Real FX, Kogevinas M, Rothman N, Silverman DT, Dyrskjøt L, Buck CB, Koutros S, Prokunina-Olsson L. (2023). Analysis of Several Common APOBEC-type Mutations in Bladder Tumors Suggests Links to Viral Infection. Cancer Prev Res 16, 561-570. CNIO Publication.
Caramelo B, Zagorac S, Corral S, Marqués M, Real FX. (2023). Cancer-associated Fibroblasts in Bladder Cancer: Origin, Biology, and Therapeutic Opportunities. Eur Urol Oncol 6, 366-375. CNIO Publication.
Font A, Domenech M, Ramirez JL, Marqués M, Benítez R, Ruiz de Porras V, Gago JL, Carrato C, Sant F, Lopez H, Castellano D, Malats N, Calle ML, Real FX. (2023). Predictive signature of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer integrating mRNA expression, taxonomic subtypes, and clinicopathological features. Front Oncol 13, 1155244. CNIO Publication.
Kloesch B, Ionasz V, Paliwal S, Hruschka N, Martinez de Villarreal J, Öllinger R, Mueller S, Dienes HP, Schindl M, Gruber ES, Stift J, Herndler-Brandstetter D, Lomberk GA, Seidler B, Saur D, Rad R, Urrutia RA, Real FX, Martinelli P. (2022). A GATA6-centred gene regulatory network involving HNFs and ?Np63 controls plasticity and immune escape in pancreatic cancer. Gut 71, 766-777. CNIO Publication.
Suarez-Cabrera C, Estudillo L, Ramón-Gil E, Martínez-Fernández M, Peral J, Rubio C, Lodewijk I, Martín de Bernardo Á, García-Escudero R, Villacampa F, Duarte J, de la Rosa F, Castellano D, Guerrero-Ramos F, Real FX, Malats N, Paramio JM, Dueñas M (2022). BlaDimiR: A Urine-based miRNA Score for Accurate Bladder Cancer Diagnosis and Follow-up. Eur Urol 82, 663-667. CNIO Publication.
Garcia-Carbonero R, Bazan-Peregrino M, Gil-Martín M, Álvarez R, Macarulla T, Riesco-Martinez MC, Verdaguer H, Guillén-Ponce C, Farrera-Sal M, Moreno R, Mato-Berciano A, Maliandi MV, Torres-Manjon S, Costa M, Del Pozo N, Martínez de Villarreal J, Real FX, Vidal N, Capella G, Alemany R, Blasi E, Blasco C, Cascalló M, Salazar R. (2022). Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors. J Immunother Cancer 10, e003255. CNIO Publication. Open Access
Chondronasiou D, Martínez de Villarreal J, Melendez E, Lynch CJ, Pozo ND, Kovatcheva M, Aguilera M, Prats N, Real FX, Serrano M. (2022). Deciphering the roadmap of in vivo reprogramming toward pluripotency. Stem Cell Reports 17, 2501-2517. CNIO Publication.
Melendez E, Chondronasiou D, Mosteiro L, Martínez de Villarreal J, Fernández-Alfara M, Lynch CJ, Grimm D, Real FX, Alcamí J, Climent N, Pietrocola F, Serrano M. (2022). Natural killer cells act as an extrinsic barrier for in vivo reprogramming. Development 149, dev200361. CNIO Publication.
Real FX, Siveke JT. (2021). Pancreatic cancer transcriptomes: molecular stratification in the adjuvant setting.. Ann Oncol 32, 133-135. CNIO Publication. Open Access
Martens S, Coolens K, Van Bulck M, Arsenijevic T, Casamitjana J, Fernandez Ruiz A, El Kaoutari A, Martinez de Villareal J, Madhloum H, Esni F, Heremans Y, Leuckx G, Heimberg H, Bouwens L, Jacquemin P, De Paep DL, In't Veld P, D'Haene N, Bouchart C, Dusetti N, Van Laethem JL, Waelput W, Lefesvre P, Real FX, Rovira M, Rooman I. (2021). Discovery and 3D imaging of a novel ?Np63-expressing basal cell type in human pancreatic ducts with implications in disease. Gut 71, 2030-2042. CNIO Publication. Open Access
Molina-Montes E, Coscia C, Gómez-Rubio P, Fernández A, Rianne Boenink R, Rava M, Márquez M, Molero X, Löhr M, Sharp L, Michalski CW, Farré A, Perea J, O'Rorke M, Greenhalf W, Iglesias M, Tardón A, Gress T, Barberà VM, Crnogorac-Jurcevic T, Muñoz-Bellvís L, Domínguez-Muñoz E, Harald Renz H, Balsells J, Costello E, Ilzarbe L, Jörg Kleeff J, Kong B, Mora J, O'Driscoll D, Poves I, Scarpa A, Yu J, Hidalgo M, Lawlor RT, Ye W, Carrato A, Real FX, Malats N, on behalf of the PanGenEU Study Investigators (2021). Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes, and obesity/BMI through causal inference and mediation analyses.. Gut 70, 319-329. CNIO Publication.
Richart L, Lapi E, Pancaldi V, Cuenca-Ardura M, Pau EC, Madrid-Mencía M, Neyret-Kahn H, Radvanyi F, Rodríguez JA, Cuartero Y, Serra F, Le Dily F, Valencia A, Marti-Renom MA, Real FX. (2021). STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells. Nucleic Acids Res 49, 11005-11021. CNIO Publication. Open Access
Lindskrog SV, Prip F, Lamy P, Taber A, Groeneveld CS, Birkenkamp-Demtröder K, Jensen JB, Strandgaard T, Nordentoft I, Christensen E, Sokac M, Birkbak NJ, Maretty L, Hermann GG, Petersen AC, Weyerer V, Grimm MO, Horstmann M, Sjödahl G, Höglund M, Steiniche T, Mogensen K, de Reyniès A, Nawroth R, Jordan B, Lin X, Dragicevic D, Ward DG, Goel A, Hurst CD, Raman JD, Warrick JI, Segersten U, Sikic D, van Kessel KEM, Maurer T, Meeks JJ, DeGraff DJ, Bryan RT, Knowles MA, Simic T, Hartmann A, Zwarthoff EC, Malmström PU, Malats N, Real FX, Dyrskjøt L (2021). An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer. Nat Commun 1, 2301. CNIO Publication. Open Access
Jermusyk A, Zhong J, Connelly KE, Gordon N, Perera S, Abdolalizadeh E, Zhang T, O'Brien A, Hoskins JW, Collins I, Eiser D, Yuan C; PanScan Consortium; PanC4 Consortium, Risch HA, Jacobs EJ, Li D, Du M, Stolzenberg-Solomon RZ, Klein AP, Smith JP, Wolpin BM, Chanock SJ, Shi J, Petersen GM, Westlake CJ, Amundadottir LT (2021). A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer. Am J Hum Genet 108, 1852-1865. CNIO Publication.
López de Maturana E, Rodríguez JA, Alonso L, Lao O, Molina-Montes E, Martín-Antoniano IA, Gómez-Rubio P, Lawlor R, Carrato A, Hidalgo M, Iglesias M, Molero X, Löhr M, Michalski C, Perea J, O'Rorke M, Barberà VM, Tardón A, Farré A, Muñoz-Bellvís L, Crnogorac-Jurcevic T, Domínguez-Muñoz E, Gress T, Greenhalf W, Sharp L, Arnes L, Cecchini L, Balsells J, Costello E, Ilzarbe L, Kleeff J, Kong B, Márquez M, Mora J, O'Driscoll D, Scarpa A, Ye W, Yu J; PanGenEU Investigators, García-Closas M, Kogevinas M, Rothman N, Silverman DT; SBC/EPICURO Investigators, Albanes D, Arslan AA, Beane-Freeman L, Bracci PM, Brennan P, Bueno-de-Mesquita B, Buring J, Canzian F, Du M, Gallinger S, Gaziano JM, Goodman PJ, Gunter M, LeMarchand L, Li D, Neale RE, Peters U, Petersen GM, Risch HA, Sánchez MJ, Shu XO, Thornquist MD, Visvanathan K, Zheng W, Chanock SJ, Easton D, Wolpin BM, Stolzenberg-Solomon RZ, Klein AP, Amundadottir LT, Marti-Renom MA, Real FX, Malats N (2021). A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer. Genome Med 13, 15. CNIO Publication. Open Access
Vangala D, Ladigan S, Liffers ST, Noseir S, Maghnouj A, Götze TM, Verdoodt B, Klein-Scory S, Godfrey L, Zowada MK, Huerta M, Edelstein DL, de Villarreal JM, Marqués M, Kumbrink J, Jung A, Schiergens T, Werner J, Heinemann V, Stintzing S, Lindoerfer D, Mansmann U, Pohl M, Teschendorf C, Bernhardt C, Wolters H, Stern J, Usta S, Viebahn R, Admard J, Casadei N, Fröhling S, Ball CR, Siveke JT, Glimm H, Tannapfel A, Schmiegel W, Hahn SA (2021). Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models.. Genome Med 13, 116. CNIO Publication.
Cobo I, Iglesias M, Flández M, Verbeke C, del Pozo N, Llorente M, Lawlor R, Luchini C, Rusev B, Scarpa A, Real FX (2021). Epithelial Nr5a2 pancreatic haploinsufficiency cooperates with mutant Kras in the development of pancreatic cystic tumors.. J Pathol 253, 174-185. CNIO Publication.
Yu J, Ploner A, Kordes M, Löhr M, Nilsson M, de Maturana MEL, Estudillo L, Renz H, Carrato A, Molero X (2021). Plasma protein biomarkers for early detection of pancreatic ductal adenocarcinoma. Int J Cancer 148, 2048-2058. CNIO Publication.
Malinova A, Veghini L, Real FX, Corbo V (2021). Cell Lineage Infidelity in PDAC Progression and Therapy Resistance. Front Cell Dev Biol 9, 795251. CNIO Publication. Open Access
Cáceres M, Quesada R, Iglesias M, Real FX, Villamonte M, de Villarreal JM, Pérez M, Andaluz A, Moll X, Berjano E, Dorcaratto D, Sánchez-Velázquez P, Grande L, Burdío F (2021). Publisher Correction: Pancreatic duct ligation reduces premalignant pancreatic lesions in a Kras model of pancreatic adenocarcinoma in mice. Sci Rep 11, 5425. CNIO Publication. Open Access
Rosato V, Gómez-Rubio P, Molina-Montes E, Márquez M, Löhr M, O'Rorke M, Michalski CW, Molero X, Farré A, Perea J, Kleeff J, Crnogorac-Jurcevic T, Greenhalf W, Ilzarbe L, Tardón A, Gress T, Barberá VM, Domínguez-Muñoz E, Muñoz-Bellvís L, Balsells J, Costello E, Iglesias M, Kong B, Mora J, O'Driscoll D, Poves I, Scarpa A, Ye W, Hidalgo M, Sharp L, Carrato A, Real FX, La Vecchia C, Malats N; PanGenEU Study Investigators. (2021). Gallbladder disease and pancreatic cancer risk: a multicentric case-control European study. Eur J Cancer Prev 30, 423-430. CNIO Publication.