Browsing by MeSH term "Pancreatic Neoplasms"
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Publication A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.(BioMed Central (BMC), 2021-02-01) López de Maturana, Evangelina; Rodríguez, Juan Antonio; Alonso, Lola; Lao, Oscar; Molina-Montes, Esther; Martín-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-Bellvís, Luís; Crnogorac-Jurcevic, Tanja; Domínguez-Muñoz, Enrique; Gress, Thomas; Greenhalf, William; Sharp, Linda; Arnes, Luís; Cecchini, Lluís; Balsells, Joaquim; Costello, Eithne; Ilzarbe, Lucas; Kleeff, Jörg; Kong, Bo; Márquez, Mirari; Mora, Josefina; O'Driscoll, Damian; Scarpa, Aldo; Ye, Weimin; Yu, Jingru; García-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 Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer.(Oxford University Press, 2019-06-01) Walsh, Naomi; Zhang, Han; Hyland, Paula L; Yang, Qi; Mocci, Evelina; Zhang, Mingfeng; Childs, Erica J; Collins, Irene; Wang, Zhaoming; Arslan, Alan A; Beane-Freeman, Laura; Bracci, Paige M; Brennan, Paul; Canzian, Federico; Duell, Eric J; Gallinger, Steven; Giles, Graham G; Goggins, Michael; Goodman, Gary E; Goodman, Phyllis J; Hung, Rayjean J; Kooperberg, Charles; Kurtz, Robert C; Malats, Nuria; LeMarchand, Loic; Neale, Rachel E; Olson, Sara H; Scelo, Ghislaine; Shu, Xiao O; Van Den Eeden, Stephen K; Visvanathan, Kala; White, Emily; Zheng, Wei; Albanes, Demetrius; Andreotti, Gabriella; Babic, Ana; Bamlet, William R; Berndt, Sonja I; Borgida, Ayelet; Boutron-Ruault, Marie-Christine; Brais, Lauren; Bueno-de-Mesquita, Bas; Buring, Julie; Chaffee, Kari G; Chanock, Stephen; Cleary, Sean; Cotterchio, Michelle; Foretova, Lenka; Fuchs, Charles; M Gaziano, J Michael; Giovannucci, Edward; Hackert, Thilo; Haiman, Christopher; Hartge, Patricia; Hasan, Manal; Helzlsouer, Kathy J; Herman, Joseph; Holcatova, Ivana; Holly, Elizabeth A; Hoover, Robert; Janout, Vladimir; Klein, Eric A; Laheru, Daniel; Lee, I-Min; Lu, Lingeng; Mannisto, Satu; Milne, Roger L; Oberg, Ann L; Orlow, Irene; Patel, Alpa V; Peters, Ulrike; Porta, Miquel; Real, Francisco X; Rothman, Nathaniel; Sesso, Howard D; Severi, Gianluca; Silverman, Debra; Strobel, Oliver; Sund, Malin; Thornquist, Mark D; Tobias, Geoffrey S; Wactawski-Wende, Jean; Wareham, Nick; Weiderpass, Elisabete; Wentzensen, Nicolas; Wheeler, William; Yu, Herbert; Zeleniuch-Jacquotte, Anne; Kraft, Peter; Li, Donghui; Jacobs, Eric J; Petersen, Gloria M; Wolpin, Brian M; Risch, Harvey A; Amundadottir, Laufey T; Yu, Kai; Klein, Alison P; Stolzenberg-Solomon, Rachael Z; NIH - National Cancer Institute (NCI) (Estados Unidos); Science Foundation Ireland; Health Research Board (Irlanda); UK Research and InnovationBACKGROUND Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. METHODS We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. RESULTS We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. CONCLUSION Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.Publication Chronic pancreatitis and lipomatosis are associated with defective function of ciliary genes in pancreatic ductal cells.(Oxford University Press, 2016-11-15) Augereau, Cécile; Collet, Louis; Vargiu, Pierfrancesco; Guerra, Carmen; Ortega Jimenez, Sagrario; Lemaigre, Frédéric P; Jacquemin, Patrick; Fondation contre le Cancer (Belgium); Universite catholique de Louvain; Centre du Cancer (Cliniques universitaires St-Luc)Genetic diseases associated with defects in primary cilia are classified as ciliopathies. Pancreatic lesions and ductal cysts are found in patients with ciliopathic polycystic kidney diseases suggesting a close connection between pancreatic defects and primary cilia. Here we investigate the role of two genes whose deletion is known to cause primary cilium defects, namely Hnf6 and Lkb1, in pancreatic ductal homeostasis. We find that mice with postnatal duct-specific deletion of Hnf6 or Lkb1 show duct dilations. Cells lining dilated ducts present shorter cilia with swollen tips, suggesting defective intraciliary transport. This is associated with signs of chronic pancreatitis, namely acinar-to-ductal metaplasia, acinar proliferation and apoptosis, presence of inflammatory infiltrates, fibrosis and lipomatosis. Our data reveal a tight association between ductal ciliary defects and pancreatitis with perturbed acinar homeostasis and differentiation. Such injuries can account for the increased risk to develop pancreatic cancer in Peutz-Jeghers patients who carry LKB1 loss-of-function mutations.Publication Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF.(Cell Press, 2019-04-15) Blasco, María Teresa; Navas, Carolina; Martín-Serrano, Guillermo; Martín-Díaz, Laura; Li, Jing; Morales-Cacho, Lucia; Esteban-Burgos, Laura; Perales-Patón, Javier; Bousquet-Mur, Emilie; Castellano, Eva; Jacob, Harrys K C; Cabras, Lavinia; Sainz, Bruno; Dusetti, Nelson; Iovanna, Juan; Sánchez-Bueno, Francisco; Hidalgo, Manuel; Khiabanian, Hossein; Rabadán, Raul; Graña Castro, Osvaldo; Lechuga C, Lechuga CG; Djurec M, Djurec M; Musteanu, Mónica; Drosten, Matthias; Ortega Jimenez, Sagrario; Mulero, Francisca; Guerra, Carmen; Barbacid, Mariano; Al-Shahrour, Fatima; Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea; Asociación Española Contra el Cáncer; Ligue Nationale Contre le Cancer (Francia); United States Department of Health and Human Services; Deutsche Forschungsgemeinschaft (Alemania); Ministerio de Ciencia e Innovación (España); Fundación La Caixa; Ministerio de Economía, Industria y Competitividad (España); Fundación AXAFive-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients.Publication Consensus document on the progression and treatment response criteria in gastroenteropancreatic neuroendocrine tumors.(2018-05-15) Merino-Casabiel, X; Aller, J; Arbizu, J; García-Figueiras, R; González, C; Grande, E; Jiménez-Fonseca, P; Sevilla, M I; Capdevila, JGastroenteropancreatic neuroendocrine tumors are a heterogeneous group of low incidence neoplasms characterized by a low proliferative activity and slow growth. Their response to targeted therapies is heterogeneous and often does not lead to tumor shrinkage. Thus, evaluation of the therapeutic response should differ from other kind of tumors. To answer relevant questions about which techniques are best in the assessment of progression or treatment response a RAND/UCLA-based consensus process was implemented. Relevant clinical questions were listed followed by a systematic search of the literature. The expert panel answered all questions with recommendations, combining available evidence and expert opinion. Recommendations were validated through a questionnaire and a participatory meeting. Expert recommendations regarding imaging tools for tumor assessment and evaluation of progression were agreed upon. Available imaging techniques were reviewed and recommendations for best patient monitoring practice and the best way to evaluate treatment response were formulated.Publication EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma.(Cell Press, 2012-09-11) Navas, Carolina; Hernández-Porras, Isabel; Schuhmacher, Alberto J; Sibilia, Maria; Guerra, Carmen; Barbacid, Mariano; Unión Europea. Comisión Europea. European Research Council (ERC); Ministerio de Economía y Competitividad (España); Fundacion de la Mutua Madrilena del Automovil; Instituto de Salud Carlos III; Fundacion Ramon Areces; Austrian Federal Government's GEN-AU program "Austro-mouse"Clinical evidence indicates that mutation/activation of EGF receptors (EGFRs) is mutually exclusive with the�presence of K-RAS oncogenes in lung and colon tumors. We have validated these observations using genetically engineered mouse models. However, development of pancreatic ductal adenocarcinomas driven by K-Ras oncogenes are totally dependent on EGFR signaling. Similar results were obtained using human pancreatic tumor cell lines. EGFRs were also essential even in the context of pancreatic injury and absence of p16Ink4a/p19Arf. Only loss of p53 made pancreatic tumors independent of EGFR signaling. Additional inhibition of PI3K and STAT3 effectively prevented proliferation of explants derived from these p53-defective pancreatic tumors. These findings may provide the bases for more rational approaches to treat pancreatic tumors in the clinic.Publication Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors.(Nature Publishing Group, 2011-11-27) Murga, Matilde; Campaner, Stefano; Lopez-Contreras, Andres J; Toledo, Luis I; Soria, Rebeca; Montaña, Maria F; Artista, Luana D'; Schleker, Thomas; Guerra, Carmen; Garcia, Elena; Barbacid, Mariano; Hidalgo, Manuel; Amati, Bruno; Fernandez-Capetillo, Oscar; German Research Foundation (DFG); European Molecular Biology Organization; Comunidad de Madrid (España); Unión Europea. Comisión Europea. European Research Council (ERC)Oncogene-induced replicative stress activates an Atr- and Chk1-dependent response, which has been proposed to be widespread in tumors. We explored whether the presence of replicative stress could be exploited for the selective elimination of cancer cells. To this end, we evaluated the impact of targeting the replicative stress-response on cancer development. In mice (Mus musculus), the reduced levels of Atr found on a mouse model of the Atr-Seckel syndrome completely prevented the development of Myc-induced lymphomas or pancreatic tumors, both of which showed abundant levels of replicative stress. Moreover, Chk1 inhibitors were highly effective in killing Myc-driven lymphomas. By contrast, pancreatic adenocarcinomas initiated by K-Ras(G12V) showed no detectable evidence of replicative stress and were nonresponsive to this therapy. Besides its impact on cancer, Myc overexpression aggravated the phenotypes of Atr-Seckel mice, revealing that oncogenes can modulate the severity of replicative stress-associated diseases.Publication Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation.(American Association for Cancer Research (AACR), 2014-07-01) Martínez-Bosch, Neus; Fernández-Barrena, Maite G; Moreno, Mireia; Ortiz-Zapater, Elena; Munné-Collado, Jessica; Iglesias, Mar; André, Sabine; Gabius, Hans-Joachim; Hwang, Rosa F; Poirier, Françoise; Navas, Carolina; Guerra, Carmen; Fernández-Zapico, Martin E; Navarro, Pilar; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Fundacio La Marato'TV3; AICR; Generalitat Catalunya; Instituto de Salud Carlos III; Ligue Nationale Contre le Cancer (Francia); EC GlycoHIT program; Fundacion Ramon Areces; Mayo Clinic Pancreatic SPORE; Mayo Clinic Center for Cell Signaling in GastroenterologyDespite some advances, pancreatic ductal adenocarcinoma (PDAC) remains generally refractory to current treatments. Desmoplastic stroma, a consistent hallmark of PDAC, has emerged as a major source of therapeutic resistance and thus potentially promising targets for improved treatment. The glycan-binding protein galectin-1 (Gal1) is highly expressed in PDAC stroma, but its roles there have not been studied. Here we report functions and molecular pathways of Gal1 that mediate its oncogenic properties in this setting. Genetic ablation of Gal1 in a mouse model of PDAC (EIa-myc mice) dampened tumor progression by inhibiting proliferation, angiogenesis, desmoplasic reaction and by stimulating a tumor-associated immune response, yielding a 20% increase in relative lifesplan. Cellular analyses in vitro and in vivo suggested these effects were mediated through the tumor microenvironment. Importantly, acinar-to-ductal metaplasia, a crucial step for initiation of PDAC, was found to be regulated by Gal1. Mechanistic investigations revealed that Gal1 promoted Hedgehog pathway signaling in PDAC cells and stromal fibroblasts as well as in Ela-myc tumors. Taken together, our findings establish a function for Gal1 in tumor-stroma crosstalk in PDAC and provide a preclinical rationale for Gal1 targeting as a microenvironment-based therapeutic strategy.Publication Genetically Engineered Mouse Models of K-Ras-Driven Lung and Pancreatic Tumors: Validation of Therapeutic Targets(Cold Spring Harbor Laboratory Press, 2018-05-01) Drosten, Matthias; Guerra, Carmen; Barbacid, Mariano; Unión Europea. Comisión Europea. European Research Council (ERC); Ministerio de Economía y Competitividad (España); Asociación Española Contra el CáncerK-RAS signaling has been intensely studied for over 40 years. Yet, as of today, no drugs have been approved to treat K-RAS mutant cancers. Since the turn of the century, scientists have used genetically engineered mouse (GEM) models to reproduce K-RAS mutant cancers in a laboratory setting to elucidate those molecular events responsible for the onset and progression of these tumors and to identify suitable therapies. In this review, we outline a brief description of available GEM models for two tumor types known to be driven by K-RAS mutations: lung adenocarcinoma and pancreatic ductal adenocarcinoma. In addition, we summarize a series of studies that have used these GEM tumor models to validate, either by genetic or pharmacological approaches, the therapeutic potential of a variety of targets, with the ultimate goal of translating these results to the clinical setting.Publication Genetically engineered mouse models of pancreatic adenocarcinoma.(Wiley, 2013-04) Guerra, Carmen; Barbacid, Mariano; Unión Europea. Comisión Europea. European Research Council (ERC); EU-Framework Programme; Ministerio de Economía y Competitividad (España)Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of human cancer for which there are no effective therapies. Deep sequencing of PDAC tumors has revealed the presence of a high number of mutations (>50) that affect at least a dozen key signaling pathways. This scenario highlights the urgent need to develop experimental models that faithfully reproduce the natural history of these human tumors in order to understand their biology and to design therapeutic approaches that might effectively interfere with their multiple mutated pathways. Over the last decade, several models, primarily based on the genetic activation of resident KRas oncogenes knocked-in within the endogenous KRas locus have been generated. These models faithfully reproduce the histological lesions that characterize human pancreatic tumors. Decoration of these models with additional mutations, primarily involving tumor suppressor loci known to be also mutated in human PDAC tumors, results in accelerated tumor progression and in the induction of invasive and metastatic malignancies. Mouse PDACs also display a desmoplastic stroma and inflammatory responses that closely resemble those observed in human patients. Interestingly, adult mice appear to be resistant to PDAC development unless the animals undergo pancreatic damage, mainly in the form of acute, chronic or even temporary pancreatitis. In this review, we describe the most representative models available to date and how their detailed characterization is allowing us to understand their cellular origin as well as the events involved in tumor progression. Moreover, their molecular dissection is starting to unveil novel therapeutic strategies that could be translated to the clinic in the very near future.Publication Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk.(American Association for Cancer Research (AACR), 2020-09-15) Yuan, Fangcheng; Hung, Rayjean J; Walsh, Naomi; Zhang, Han; Platz, Elizabeth A; Wheeler, William; Song, Lei; Arslan, Alan A; Beane Freeman, Laura E; Bracci, Paige; Canzian, Federico; Du, Mengmeng; Gallinger, Steven; Giles, Graham G; Goodman, Phyllis J; Kooperberg, Charles; Le Marchand, Loic; Neale, Rachel E; Rosendahl, Jonas; Scelo, Ghislaine; Shu, Xiao-Ou; Visvanathan, Kala; White, Emily; Zheng, Wei; Albanes, Demetrius; Amiano, Pilar; Andreotti, Gabriella; Babic, Ana; Bamlet, William R; Berndt, Sonja I; Brennan, Paul; Bueno-de-Mesquita, Bas; Buring, Julie E; Campbell, Peter T; Chanock, Stephen J; Fuchs, Charles S; Gaziano, J Michael; Goggins, Michael G; Hackert, Thilo; Hartge, Patricia; Hassan, Manal M; Holly, Elizabeth A; Hoover, Robert N; Katzke, Verena; Kirsten, Holger; Kurtz, Robert C; Lee, I-Min; Malats, Nuria; Milne, Roger L; Murphy, Neil; Ng, Kimmie; Oberg, Ann L; Porta, Miquel; Rabe, Kari G; Real Arribas, Francisco; Rothman, Nathaniel; Sesso, Howard D; Silverman, Debra T; Thompson, Ian M; Wactawski-Wende, Jean; Wang, Xiaoliang; Wentzensen, Nicolas; Wilkens, Lynne R; Yu, Herbert; Zeleniuch-Jacquotte, Anne; Shi, Jianxin; Duell, Eric J; Amundadottir, Laufey T; Li, Donghui; Petersen, Gloria M; Wolpin, Brian M; Risch, Harvey A; Yu, Kai; Klein, Alison P; Stolzenberg-Solomon, Rachael; NIH - National Cancer Institute (NCI) (Estados Unidos)Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10-6, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. SIGNIFICANCE: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.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, Matías; 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.Publication Incidence and Survival Trends of Pancreatic Cancer in Girona: Impact of the Change in Patient Care in the Last 25 Years.(Multidisciplinary Digital Publishing Institute (MDPI), 2020-12-19) García-Velasco, Adelaida; Zacarías-Pons, Lluís; Teixidor, Helena; Valeros, Marc; Liñan, Raquel; Carmona-Garcia, M Carmen; Puigdemont, Montse; Carbajal, Walter; Guardeño, Raquel; Malats, Nuria; Duell, Eric; Marcos-Gragera, Rafael(1) Background: We investigated the incidence and survival trends for pancreatic cancer (PC) over the last 25 years in the Girona region, Catalonia, Spain; (2) Methods: Data were extracted from the population-based Girona Cancer Registry. Incident PC cases during 1994-2015 were classified using the International Classification of Diseases for Oncology Third Edition (ICD-O-3). Incidence rates age-adjusted to the European standard population (ASRE) and world standard population (ASRW) were obtained. Trends were assessed using the estimated annual percentage of change (EAPC) of the ASRE13. Observed and relative survivals (RS) were estimated with the Kaplan-Meier and Pohar Perme methods, respectively; (3) Results: We identified 1602 PC incident cases. According to histology, 44.4% of cases were exocrine PC, 4.1% neuroendocrine, and 51.1% malignant-non-specified. The crude incidence rate (CR) for PC was 11.43 cases-per-100,000 inhabitants/year. A significant increase of incidence with age and over the study period was observed. PC overall 5-year RS was 7.05% (95% confidence interval (CI) 5.63; 8.84). Longer overall survival was observed in patients with neuroendocrine tumours (5-year RS 61.45%; 95% CI 47.47; 79.55). Trends in 5-year RS for the whole cohort rose from 3.27% (95% CI 1.69-6.35) in 1994-1998 to 13.1% (95% CI 9.98; 17.2) in 2010-2015; (4) Conclusions: Incidence rates of PC in Girona have increased in the last two decades. There is a moderate but encouraging increase in survival thorough the study period. These results can be used as baseline for future research.Publication Inflammation and stem markers association to PIM1/PIM2 kinase-induced tumors in breast and uterus(Impact Journals, 2017-08-29) Jiménez-García, Manuel-Pedro; Lucena-Cacace, Antonio; Robles-Frías, María-José; Ferrer, Irene; Narlik-Grassow, Maja; Blanco-Aparicio, Carmen; Carnero, Amancio; Ministerio de Economía y Competitividad (España); Centro de Investigación Biomedica en Red - CIBER; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Regional Government of Andalusia (España); Asociación Española Contra el CáncerThe PIM family of Ser/Thr kinase proteins has been implicated in tumorigenesis at different levels. PIM proteins are overexpressed in several tumor types and have been associated with chemoresistance. However, their role in hormone-dependent female tissues has not been explored, especially in the uterus, breast and ovary. We generated conditional transgenic mice with confined expression of human PIM1 or PIM2 genes in these tissues. We characterized the tumoral response to these genetic alterations corroborating their role as oncogenes since they induce hyperproliferation in all tissues and tumors in mammary gland and uterus. Furthermore, we observed a high degree of inflammatory infiltration in these tissues of transgenic mice accompanied by NFAT and mTOR activation and IL6 expression. Moreover, PIM1/2 were overexpressed in human breast, uterine and ovarian tumors, correlating with inflammatory features and stem cell markers. Our data suggest that PIM1/2 kinase overexpression provoke tissue alterations and a large IL6-dependent inflammatory response that may act synergistically during the process of tumorigenesis. The possible end-point is an increased percentage of cancer stem cells, which may be partly responsible for the therapy resistance found in tumors overexpressing PIM kinases.Publication MicroRNA signature and integrative omics analyses define prognostic clusters and key pathways driving prognosis in patients with neuroendocrine neoplasms(Wiley, 2023-04) Soldevilla, Beatriz; Lens-Pardo, Alberto; Espinosa-Olarte, Paula; Carretero-Puche, Carlos; Molina-Pinelo, Sonia; Robles, Carlos; Benavent, Marta; Gomez-Izquierdo, Lourdes; Fierro-Fernández, Marta; Morales-Burgo, Patricia; Jimenez-Fonseca, Paula; Anton-Pascual, Beatriz; Rodriguez-Gil, Yolanda; Teijo-Quintans, Ana; La Salvia, Anna; Rubio-Cuesta, Beatriz; Riesco-Martínez, Maria C; Garcia-Carbonero, Rocio; García-Carbonero, Rocio; Lens‐Pardo, Alberto; Espinosa‐Olarte, Paula; Carretero‐Puche, Carlos; Molina‐Pinelo, Sonia; Gomez‐Izquierdo, Lourdes; Fierro‐Fernández, Marta; Morales‐Burgo, Patricia; Jimenez‐Fonseca, Paula; Anton‐Pascual, Beatriz; Rodriguez‐Gil, Yolanda; Teijo‐Quintans, Ana; Rubio‐Cuesta, Beatriz; Riesco‐Martínez, Maria C.; Garcia‐Carbonero, Rocio; ISCIII-Red de Biobancos y Biomodelos; Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Junta de AndaluciaNeuroendocrine neoplasms (NENs) are mutationally quiet (low number of mutations/Mb), and epigenetic mechanisms drive their development and progression. We aimed at comprehensively characterising the microRNA (miRNA) profile of NENs, and exploring downstream targets and their epigenetic modulation. In total, 84 cancer-related miRNAs were analysed in 85 NEN samples from lung and gastroenteropancreatic (GEP) origin, and their prognostic value was evaluated by univariate and multivariate models. Transcriptomics (N�=�63) and methylomics (N�=�30) were performed to predict miRNA target genes, signalling pathways and regulatory CpG sites. Findings were validated in The Cancer Genome Atlas cohorts and in NEN cell lines. We identified a signature of eight miRNAs that stratified patients in three prognostic groups (5-year survival of 80%, 66% and 36%). Expression of the eight-miRNA gene signature correlated with 71 target genes involved in PI3K-Akt and TNF?-NF-kB signalling. Of these, 28 were associated with survival and validated in silico and in vitro. Finally, we identified five CpG sites involved in the epigenetic regulation of these eight miRNAs. In brief, we identified an 8-miRNA signature able to predict survival of patients with GEP and lung NENs, and identified genes and regulatory mechanisms driving prognosis in NEN patients.Publication Monitoring vascular normalization induced by antiangiogenic treatment with (18)F-fluoromisonidazole-PET(Wiley, 2016-05) Hernandez-Agudo, Elena; Mondejar, Tamara; Soto-Montenegro, Maria Luisa; Megias Vazquez, Diego; Mouron, Silvana Andrea; Sanchez, Jesus; Hidalgo, Manuel; Lopez-Casas, Pedro Pablo; Mulero Francisca, Francisca; Desco, Manuel; Quintela Fandino, Miguel Angel; Unión Europea; Asociación Española Contra el Cáncer; Ministerio de Sanidad y Consumo (España)BACKGROUND: Rationalization of antiangiogenics requires biomarkers. Vascular re-normalization is one widely accepted mechanism of action for this drug class. The interstitium of tumors with abnormal vasculature is hypoxic. We sought to track vascular normalization with (18)F-misonidazole ([18F]-FMISO, a probe that detects hypoxia) PET, in response to window-of-opportunity (WoO) treatment with the antiangiogenic dovitinib. METHODS: Two patient-derived pancreas xenografts (PDXs; Panc215 and Panc286) and the spontaneous breast cancer model MMTV-PyMT were used. Animals were treated during 1 week of WoO treatment with vehicle or dovitinib, preceded and followed by [18F]-FMISO-PET, [18F]-FDG-PET, and histologic assessment (dextran extravasation, hypoxia and microvessel staining, and necrosis, cleaved caspase-3 and Ki67 measurements). After WoO treatment, gemcitabine (pancreas)/adriamycin (breast) or vehicle was added and animals were treated until the humane endpoint. Tumor growth inhibition (TGI) and survival were the parameters studied. RESULTS: [18F]-FMISO SUV did not change after dovitinib-WoO treatment compared to vehicle-WoO (0.54 vs. 0.6) treatment in Panc215, but it decreased significantly in Panc286 (0.58 vs. 1.18; P < 0.05). In parallel, 10-KDa perivascular dextran extravasation was not reduced with dovitinib or vehicle-WoO treatment in Panc215, but it was reduced in Panc286. Whereas the addition of dovitinib to gemcitabine was indifferent in Panc215, it increased TGI in Panc286 (TGI switched from -59% to +49%). [18F]-FMISO SUV changes were accompanied by an almost 100% increase in interstitial gemcitabine delivery (665-1260 ng/mL). The results were validated in the PyMT model. CONCLUSIONS: [18F]-FMISO accurately monitored vascular re-normalization and improved interstitial chemotherapy delivery.Publication Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.(Nature Publishing Group, 2015-06) Costa-Silva, Bruno; Aiello, Nicole M; Ocean, Allyson J; Singh, Swarnima; Zhang, Haiying; Thakur, Basant Kumar; Becker, Annette; Hoshino, Ayuko; Mark, Milica Tešić; Molina, Henrik; Xiang, Jenny; Zhang, Tuo; Theilen, Till-Martin; García-Santos, Guillermo; Williams, Caitlin; Ararso, Yonathan; Huang, Yujie; Rodrigues, Gonçalo; Shen, Tang-Long; Labori, Knut Jørgen; Lothe, Inger Marie Bowitz; Kure, Elin H; Hernandez, Jonathan; Doussot, Alexandre; Ebbesen, Saya H; Grandgenett, Paul M; Hollingsworth, Michael A; Jain, Maneesh; Mallya, Kavita; Batra, Surinder K; Jarnagin, William R; Schwartz, Robert E; Matei, Irina; Peinado, Héctor; Stanger, Ben Z; Bromberg, Jacqueline; Lyden, DavidPancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.Publication Pancreatic cancer transcriptomes: molecular stratification in the adjuvant setting.(Elsevier, 2021-02) Real Arribas, Francisco; Siveke, J T; German Cancer Consortium (Alemania); Deutsche Forschungsgemeinschaft (Alemania); Deutsche Krebshilfe; Ministerio de Ciencia e Innovación (España)Publication Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence.(Cell Press, 2011-06-14) Guerra, Carmen; Collado, Manuel; Navas, Carolina; Schuhmacher, Alberto J; Hernández-Porras, Isabel; Cañamero, Marta; Rodriguez-Justo, Manuel; Serrano, Manuel; Barbacid, Mariano; Unión Europea. Comisión Europea. European Research Council (ERC); Comunidad de Madrid (España); Ministerio de Ciencia y Competitividad (España); Marcelino Botin Foundation; UCLH/UCL Comprehensive Biomedical Research Centre (London, UK)Pancreatic acinar cells of adult mice (?P60) are resistant to transformation by some of the most robust oncogenic insults including expression of K-Ras oncogenes and loss of p16Ink4a/p19Arf or Trp53 tumor suppressors. Yet, these acinar cells yield pancreatic intraepithelial neoplasias (mPanIN) and ductal adenocarcinomas (mPDAC) if exposed to limited bouts of non-acute pancreatitis, providing they harbor K-Ras oncogenes. Pancreatitis contributes to tumor progression by abrogating the senescence barrier characteristic of low-grade mPanINs. Attenuation of pancreatitis-induced inflammation also accelerates tissue repair and thwarts mPanIN expansion. Patients with chronic pancreatitis display senescent PanINs, providing they have received antiinflammatory drugs. These results support the concept that antiinflammatory treatment of people diagnosed with pancreatitis may reduce their risk of developing PDAC.Publication Reply: 'Comments on Stromal disrupting effects of nab-paclitaxel in pancreatic cancer'.(Springer, 2014-10-14) Alvarez, R; Musteanu, M; Garcia-Garcia, E; Lopez-Casas, P P; Megias, D; Guerra, Carmen; Muñoz, M; Quijano, Y; Cubillo, A; Rodriguez-Pascual, J; Plaza, C; de Vicente, E; Prados, S; Tabernero, S; Barbacid, Mariano; Lopez-Rios, F; Hidalgo, M; Unión Europea. Comisión Europea. European Research Council (ERC)