Browsing by MeSH term "Carcinoma, Pancreatic Ductal"
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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 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 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 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 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 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 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 Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors(National Academy of Sciences, 2018-02-06) Djurec, Magdolna; Graña Castro, Osvaldo; Lee, Albert; Troulé, Kevin; Espinet, Elisa; Cabras, Lavinia; Navas, Carolina; Blasco, María Teresa; Martín-Díaz, Laura; Burdiel, Miranda; Li, Jing; Liu, Zhaoqi; Vallespinós, Mireia; Sanchez-Bueno, Francisco; Sprick, Martin R; Trumpp, Andreas; Sainz, Bruno; Al-Shahrour, Fatima; Rabadan, Raul; Guerra, Carmen; Barbacid, Mariano; German Cancer Research Center; Unión Europea. Comisión Europea. European Research Council (ERC); Ministerio de Economía y Competitividad (España); Asociación Española Contra el Cáncer; Fundación La Caixa; Fundación AXAPancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of abundant desmoplastic stroma primarily composed of cancer-associated fibroblasts (CAFs). It is generally accepted that CAFs stimulate tumor progression and might be implicated in drug resistance and immunosuppression. Here, we have compared the transcriptional profile of PDGFRα+ CAFs isolated from genetically engineered mouse PDAC tumors with that of normal pancreatic fibroblasts to identify genes potentially implicated in their protumorigenic properties. We report that the most differentially expressed gene, Saa3, a member of the serum amyloid A (SAA) apolipoprotein family, is a key mediator of the protumorigenic activity of PDGFRα+ CAFs. Whereas Saa3-competent CAFs stimulate the growth of tumor cells in an orthotopic model, Saa3-null CAFs inhibit tumor growth. Saa3 also plays a role in the cross talk between CAFs and tumor cells. Ablation of Saa3 in pancreatic tumor cells makes them insensitive to the inhibitory effect of Saa3-null CAFs. As a consequence, germline ablation of Saa3 does not prevent PDAC development in mice. The protumorigenic activity of Saa3 in CAFs is mediated by Mpp6, a member of the palmitoylated membrane protein subfamily of the peripheral membrane-associated guanylate kinases (MAGUK). Finally, we interrogated whether these observations could be translated to a human scenario. Indeed, SAA1, the ortholog of murine Saa3, is overexpressed in human CAFs. Moreover, high levels of SAA1 in the stromal component correlate with worse survival. These findings support the concept that selective inhibition of SAA1 in CAFs may provide potential therapeutic benefit to PDAC patients.Publication Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk(National Academy of Sciences, 2018-04-17) Orozco, Carlos A; Martinez-Bosch, Neus; Guerrero, Pedro E; Vinaixa, Judith; Dalotto-Moreno, Tomás; Iglesias, Mar; Moreno, Mireia; Djurec, Magdolna; Poirier, Françoise; Gabius, Hans-Joachim; Fernandez-Zapico, Martin E; Hwang, Rosa F; Guerra, Carmen; Rabinovich, Gabriel A; Navarro, Pilar; Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Asociación Española de Pancreatologia; Government of Catalonia (España); Colciencias; University of Buenos Aires (Argentina); Sales Foundation; Bunge and Born Foundation; National Scientific and Technical Research Council (Argentina)Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela-KrasG12Vp53 -/- ) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.Publication Temporality of body mass index, blood tests, comorbidities and medication use as early markers for pancreatic ductal adenocarcinoma (PDAC): a nested case-control study(BMJ Publishing Group, 2023-03) Tan, Pui San; Garriga, Cesar; Clift, Ashley; Liao, Weiqi; Patone, Martina; Coupland, Carol; Bashford-Rogers, Rachael; Sivakumar, Shivan; Hippisley-Cox, Julia; Cancer Research UK (Reino Unido)Objective: Prior studies identified clinical factors associated with increased risk of pancreatic ductal adenocarcinoma (PDAC). However, little is known regarding their time-varying nature, which could inform earlier diagnosis. This study assessed temporality of body mass index (BMI), blood-based markers, comorbidities and medication use with PDAC risk. Design: We performed a population-based nested case-control study of 28 137 PDAC cases and 261 219 matched-controls in England. We described the associations of biomarkers with risk of PDAC using fractional polynomials and 5-year time trends using joinpoint regression. Associations with comorbidities and medication use were evaluated using conditional logistic regression. Results: Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while following a U-shaped relationship for BMI and haemoglobin. Five-year trends showed biphasic BMI decrease and HbA1c increase prior to PDAC; early-gradual changes 2-3 years prior, followed by late-rapid changes 1-2 years prior. Liver markers and blood counts (white blood cell, platelets) showed monophasic rapid-increase approximately 1 year prior. Recent diagnosis of pancreatic cyst, pancreatitis, type 2 diabetes and initiation of certain glucose-lowering and acid-regulating therapies were associated with highest risk of PDAC. Conclusion: Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while followed a U-shaped relationship for BMI and haemoglobin. BMI and HbA1c derange biphasically approximately 3 years prior while liver markers and blood counts (white blood cell, platelets) derange monophasically approximately 1 year prior to PDAC. Profiling these in combination with their temporality could inform earlier PDAC diagnosis.Publication The epigenetic regulators Bmi1 and Ring1B are differentially regulated in pancreatitis and pancreatic ductal adenocarcinoma.(Wiley, 2009-10) Martínez-Romero, Carles; Rooman, Ilse; Skoudy, Anouchka; Guerra, Carmen; Molero, Xavier; González, Ana; Iglesias, Mar; Lobato, Tania; Bosch, Almudena; Barbacid, Mariano; Real Arribas, Francisco; Hernández-Muñoz, Inmaculada; Instituto de Salud Carlos III; Biomed Programme; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT); European Union (EU)Chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC) are associated with major changes in cell differentiation. These changes may be at the basis of the increased risk for PDAC among patients with chronic pancreatitis. Polycomb proteins are epigenetic silencers expressed in adult stem cells; up-regulation of Polycomb proteins has been reported to occur in a variety of solid tumours such as colon and breast cancer. We hypothesized that Polycomb might play a role in preneoplastic states in the pancreas and in tumour development/progression. To test these ideas, we determined the expression of PRC1 complex proteins (Bmi1 and Ring1b) during pancreatic development and in pancreatic tissue from mouse models of disease: acute and chronic pancreatic injury, duct ligation, and in K-Ras(G12V) conditional knock-in and caerulein-treated K-Ras(G12V) mice. The study was extended to human pancreatic tissue samples. To obtain mechanistic insights, Bmi1 expression in cells undergoing in vitro exocrine cell metaplasia and the effects of Bmi1 depletion in an acinar cancer cell line were studied. We found that Bmi1 and Ring1B are expressed in pancreatic exocrine precursor cells during early development and in ductal and islet cells-but not acinar cells-in the adult pancreas. Bmi1 expression was induced in acinar cells during acute injury, in acinar-ductal metaplastic lesions, as well as in pancreatic intraepithelial neoplasia (PanIN) and PDAC. In contrast, Ring1B expression was only significantly and persistently up-regulated in high-grade PanINs and in PDAC. Bmi1 knockdown in cultured acinar tumour cells led to changes in the expression of various digestive enzymes. Our results suggest that Bmi1 and Ring1B are modulated in pancreatic diseases and could contribute differently to tumour development.Publication The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.(BMJ Publishing Group, 2024-08-08) López-Gil, Juan Carlos; García-Silva, Susana; Ruiz-Cañas, Laura; Navarro, Diego; Palencia-Campos, Adrián; Giráldez-Trujillo, Antonio; Earl, Julie; Dorado, Jorge; Gómez-López, Gonzalo; Monfort-Vengut, Ana; Alcalá, Sonia; Gaida, Matthias M; García-Mulero, Sandra; Cabezas-Sáinz, Pablo; Batres-Ramos, Sandra; Barreto, Emma; Sánchez-Tomero, Patricia; Vallespinós, Mireia; Ambler, Leah; Lin, Meng-Lay; Aicher, Alexandra; García García de Paredes, Ana; de la Pinta, Carolina; Sanjuanbenito, Alfonso; Ruz-Caracuel, Ignacio; Rodríguez-Garrote, Mercedes; Guerra, Carmen; Carrato, Alfredo; de Cárcer, Guillermo; Sánchez, Laura; Nombela-Arrieta, César; Espinet, Elisa; Sanchez-Arevalo Lobo, Víctor Javier; Heeschen, Christopher; Sainz, Bruno; Fundación La Caixa; EMBO Scientific Exchange Fellowship; Juan de la Cierva Formacion; Fero Foundation Grant; Ministerio de Economía y Competitividad (España); Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomédica en Red - CIBERONC (Cáncer); Xunta de Galicia (España); University of Zurich; German Research Foundation (DFG); Unión Europea. Comisión Europea. European Research Council (ERC); Fondazione AIRC per la ricerca sul cancro; Shanghai Municipal Education Commission (SHMEC); National Natural Science Foundation of China (NSFC)OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. DESIGN: We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. RESULTS: Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNF?)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. CONCLUSIONS: This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.