Browsing by MeSH term "Pancreas"
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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 Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice.(American Society for Clinical Investigation (ASCI), 2004-05) Iglesias, Ainhoa; Murga, Matilde; Laresgoiti, Usua; Skoudy, Anouchka; Bernales, Irantzu; Fullaondo, Asier; Moreno, Bernardino; Lloreta, José; Field, Seth J; Real, Francisco X; Zubiaga, Ana ME2F transcription factors are thought to be key regulators of cell growth control. Here we use mutant mouse strains to investigate the function of E2F1 and E2F2 in vivo. E2F1/E2F2 compound-mutant mice develop nonautoimmune insulin-deficient diabetes and exocrine pancreatic dysfunction characterized by endocrine and exocrine cell dysplasia, a reduction in the number and size of acini and islets, and their replacement by ductal structures and adipose tissue. Mutant pancreatic cells exhibit increased rates of DNA replication but also of apoptosis, resulting in severe pancreatic atrophy. The expression of genes involved in DNA replication and cell cycle control was upregulated in the E2F1/E2F2 compound-mutant pancreas, suggesting that their expression is repressed by E2F1/E2F2 activities and that the inappropriate cell cycle found in the mutant pancreas is likely the result of the deregulated expression of these genes. Interestingly, the expression of ductal cell and adipocyte differentiation marker genes was also upregulated, whereas expression of pancreatic cell marker genes were downregulated. These results suggest that E2F1/E2F2 activity negatively controls growth of mature pancreatic cells and is necessary for the maintenance of differentiated pancreatic phenotypes in the adult.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 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 Loss of GATA4 causes ectopic pancreas in the stomach.(Wiley, 2020-04) Rodríguez-Seguel, Elisa; Villamayor, Laura; Arroyo, Noelia; De Andrés, Mónica P; Real Arribas, Francisco; Martín, Franz; Cano, David A; Rojas, Anabel; Ministerio de Ciencia y Universidades (España)Pancreatic heterotopia is defined as pancreatic tissue outside its normal location in the body and anatomically separated from the pancreas. In this work we have analyzed the stomach glandular epithelium of Gata4 flox/flox ; Pdx1-Cre mice (Gata4KO mice). We found that Gata4KO glandular epithelium displays an atypical morphology similar to the cornified squamous epithelium and exhibits upregulation of forestomach markers. The developing gastric units fail to form properly, and the glandular epithelial cells do not express markers of gastric gland in the absence of GATA4. Of interest, the developing glands of the Gata4KO stomach express pancreatic cell markers. Furthermore, a mass of pancreatic tissue located in the subserosa of the Gata4KO stomach is observed at adult stages. Heterotopic pancreas found in Gata4-deficient mice contains all three pancreatic cell lineages: ductal, acinar, and endocrine. Moreover, Gata4 expression is downregulated in ectopic pancreatic tissue of some human biopsy samples. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.Publication Loss of p27Kip¹ promotes metaplasia in the pancreas via the regulation of Sox9 expression.(Impact Journals, 2015-11-03) Jeannot, Pauline; Callot, Caroline; Baer, Romain; Duquesnes, Nicolas; Guerra, Carmen; Guillermet-Guibert, Julie; Bachs, Oriol; Besson, Arnaud; Estonian Research Council; Australian Research Council; Fondation ARC pour la recherche sur le cancer; Institut National du Cancer (INCA) Francep27Kip1 (p27) is a negative regulator of proliferation and a tumor suppressor via the inhibition of cyclin-CDK activity in the nucleus. p27 is also involved in the regulation of other cellular processes, including transcription by acting as a transcriptional co-repressor. Loss of p27 expression is frequently observed in pancreatic adenocarcinomas in human and is associated with decreased patient survival. Similarly, in a mouse model of K-Ras-driven pancreatic cancer, loss of p27 accelerates tumor development and shortens survival, suggesting an important role for p27 in pancreatic tumorigenesis. Here, we sought to determine how p27 might contribute to early events leading to tumor development in the pancreas. We found that K-Ras activation in the pancreas causes p27 mislocalization at pre-neoplastic stages. Moreover, loss of p27 or expression of a mutant p27 that does not bind cyclin-CDKs causes the mislocalization of several acinar polarity markers associated with metaplasia and induces the nuclear expression of Sox9 and Pdx1 two transcription factors involved in acinar-to-ductal metaplasia. Finally, we found that p27 directly represses transcription of Sox9, but not that of Pdx1. Thus, our results suggest that K-Ras activation, the earliest known event in pancreatic carcinogenesis, may cause loss of nuclear p27 expression which results in derepression of Sox9, triggering reprogramming of acinar cells and metaplasia.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 Reprogramming in vivo produces teratomas and iPS cells with totipotency features.(Nature Publishing Group, 2013-10-17) Abad, María; Mosteiro, Lluc; Pantoja, Cristina; Cañamero, Marta; Rayon, Teresa; Ors, Inmaculada; Graña, Osvaldo; Megías, Diego; Dominguez, Orlando; Martinez Garcia, Maria Dolores; Manzanares, Miguel; Ortega Jimenez, Sagrario; Serrano, Manuel; Ministerio de Economía e Innovación (España); Fundación Ramón Areces; Fundación ProCNIC; Fundación AXA; Comunidad de Madrid (España)Reprogramming of adult cells to generate induced pluripotent stem cells (iPS cells) has opened new therapeutic opportunities; however, little is known about the possibility of in vivo reprogramming within tissues. Here we show that transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice results in teratomas emerging from multiple organs, implying that full reprogramming can occur in vivo. Analyses of the stomach, intestine, pancreas and kidney reveal groups of dedifferentiated cells that express the pluripotency marker NANOG, indicative of in situ reprogramming. By bone marrow transplantation, we demonstrate that haematopoietic cells can also be reprogrammed in vivo. Notably, reprogrammable mice present circulating iPS cells in the blood and, at the transcriptome level, these in vivo generated iPS cells are closer to embryonic stem cells (ES cells) than standard in vitro generated iPS cells. Moreover, in vivo iPS cells efficiently contribute to the trophectoderm lineage, suggesting that they achieve a more plastic or primitive state than ES cells. Finally, intraperitoneal injection of in vivo iPS cells generates embryo-like structures that express embryonic and extraembryonic markers. We conclude that reprogramming in vivo is feasible and confers totipotency features absent in standard iPS or ES cells. These discoveries could be relevant for future applications of reprogramming in regenerative medicine.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 The Atypical Cannabinoid Abn-CBD Reduces Inflammation and Protects Liver, Pancreas, and Adipose Tissue in a Mouse Model of Prediabetes and Non-alcoholic Fatty Liver Disease(Frontiers Media, 2020-03-06) Romero-Zerbo, Silvana Y.; García-Fernández, María; Espinosa-Jiménez, Vanesa; Pozo-Morales, Macarena; Escamilla-Sánchez, Alejandro; Sánchez-Salido, Lourdes; Lara, Estrella; Cobo-Vuilleumier, Nadia; Rafacho, Alex; Olveira, Gabriel; Rojo-Martínez, Gemma; Gauthier, Benoit R.; González-Mariscal, Isabel; Bermúdez-Silva, Francisco J.; [Romero-Zerbo,SY; Espinosa-Jiménez,V; Pozo-Morales,M; Sánchez-Salido,L; Olveira,G; Rojo-Martínez,G;González-Mariscal,I; Bermúdez-Silva;FJ] UGC Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Regional de Málaga, Universidad de Málaga, Málaga, Spain. [García-Fernández,M; Lara,E;] Departamento de Fisiología Humana, Facultad de Medicina, Instituto de Investigación Biomédica de Málaga-IBIMA, Universidad de Málaga, Málaga, Spain. [Escamilla-Sánchez,A] Plataforma de Microscopía, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain. [Cobo-Vuilleumier,N; Gauthier,BR] Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain. [Rafacho,A] Laboratory of Investigation in Chronic Diseases - LIDoC, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, Brazil. [Olveira,G; Rojo-Martínez,G; Gauthier,BR; Bermúdez-Silva,FJ] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.Background and Aims: The synthetic atypical cannabinoid Abn-CBD, a cannabidiol (CBD) derivative, has been recently shown to modulate the immune system in different organs, but its impact in obesity-related meta-inflammation remains unstudied. We investigated the effects of Abn-CBD on metabolic and inflammatory parameters utilizing a diet-induced obese (DIO) mouse model of prediabetes and non-alcoholic fatty liver disease (NAFLD). Materials and Methods: Ten-week-old C57Bl/6J mice were fed a high-fat diet for 15 weeks, following a 2-week treatment of daily intraperitoneal injections with Abn-CBD or vehicle. At week 15 mice were obese, prediabetic and developed NAFLD. Body weight and glucose homeostasis were monitored. Mice were euthanized and blood, liver, adipose tissue and pancreas were collected and processed for metabolic and inflammatory analysis. Results: Body weight and triglycerides profiles in blood and liver were comparable between vehicle- and Abn-CBD-treated DIO mice. However, treatment with Abn-CBD reduced hyperinsulinemia and markers of systemic low-grade inflammation in plasma and fat, also promoting white adipose tissue browning. Pancreatic islets from Abn-CBD-treated mice showed lower apoptosis, inflammation and oxidative stress than vehicle-treated DIO mice, and beta cell proliferation was induced. Furthermore, Abn-CBD lowered hepatic fibrosis, inflammation and macrophage infiltration in the liver when compared to vehicle-treated DIO mice. Importantly, the balance between hepatocyte proliferation and apoptosis was improved in Abn-CBD-treated compared to vehicle-treated DIO mice. Conclusions: These results suggest that Abn-CBD exerts beneficial immunomodulatory actions in the liver, pancreas and adipose tissue of DIO prediabetic mice with NAFLD, thus protecting tissues. Therefore, Abn-CBD and related compounds could represent novel pharmacological strategies for managing obesity-related metabolic disorders.Publication The contribution of cohesin-SA1 to gene expression and chromatin architecture in two murine tissues(Oxford University Press, 2015-03-31) Cuadrado Garcia, Ana; Remeseiro, Silvia; Graña Castro, Osvaldo; Pisano, David G; Losada, Ana; Ministerio de Economía y Competitividad (España); Fundación La CaixaCohesin, which in somatic vertebrate cells consists of SMC1, SMC3, RAD21 and either SA1 or SA2, mediates higher-order chromatin organization. To determine how cohesin contributes to the establishment of tissue-specific transcriptional programs, we compared genome-wide cohesin distribution, gene expression and chromatin architecture in cerebral cortex and pancreas from adult mice. More than one third of cohesin binding sites differ between the two tissues and these show reduced overlap with CCCTC-binding factor (CTCF) and are enriched at the regulatory regions of tissue-specific genes. Cohesin/CTCF sites at active enhancers and promoters contain, at least, cohesin-SA1. Analyses of chromatin contacts at the Protocadherin (Pcdh) and Regenerating islet-derived (Reg) gene clusters, mostly expressed in brain and pancreas, respectively, revealed remarkable differences that correlate with the presence of cohesin. We could not detect significant changes in the chromatin contacts at the Pcdh locus when comparing brains from wild-type and SA1 null embryos. In contrast, reduced dosage of SA1 altered the architecture of the Reg locus and decreased the expression of Reg genes in the pancreas of SA1 heterozygous mice. Given the role of Reg proteins in inflammation, such reduction may contribute to the increased incidence of pancreatic cancer observed in these animals.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 Wilms' tumor suppressor gene regulates pancreas homeostasis and repair.(2019-02-14) Ariza, Laura; Rojas, Anabel; Muñoz-Chápuli, Ramón; Carmona, RitaThe Wilms' tumor suppressor gene (Wt1) encodes a zinc finger transcription factor that plays an essential role in the development of kidneys, gonads, spleen, adrenals and heart. Recent findings suggest that WT1 could also be playing physiological roles in adults. Systemic deletion of WT1 in mice provokes a severe deterioration of the exocrine pancreas, with mesothelial disruption, E-cadherin downregulation, disorganization of acinar architecture and accumulation of ascitic transudate. Despite this extensive damage, pancreatic stellate cells do not become activated and lose their canonical markers. We observed that pharmacological induction of pancreatitis in normal mice provokes de novo expression of WT1 in pancreatic stellate cells, concomitant with their activation. When pancreatitis was induced in mice after WT1 ablation, pancreatic stellate cells expressed WT1 and became activated, leading to a partial rescue of the acinar structure and the quiescent pancreatic stellate cell population after recovery from pancreatitis. We propose that WT1 modulates through the RALDH2/retinoic acid axis the restabilization of a part of the pancreatic stellate cell population and, indirectly, the repair of the pancreatic architecture, since quiescent pancreatic stellate cells are required for pancreas stability and repair. Thus, we suggest that WT1 plays novel and essential roles for the homeostasis of the adult pancreas and, through its upregulation in pancreatic stellate cells after a damage, for pancreatic regeneration. Due to the growing importance of the pancreatic stellate cells in physiological and pathophysiological conditions, these novel roles can be of translational relevance.Publication Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas.(Nature Publishing Group, 2018-02-22) Cobo, Isidoro; Martinelli, Paola; Flández, Marta; Bakiri, Latifa; Zhang, Mingfeng; Carrillo-de-Santa-Pau, Enrique; Jia, Jinping; Sánchez-Arévalo Lobo, Víctor J; Megías, Diego; Felipe, Irene; Del Pozo, Natalia; Millán, Irene; Thommesen, Liv; Bruland, Torunn; Olson, Sara H; Smith, Jill; Schoonjans, Kristina; Bamlet, William R; Petersen, Gloria M; Malats, Núria; Amundadottir, Laufey T; Wagner, Erwin F; Real Arribas, Francisco; Ministerio de Economía y Competitividad (España); European Union (EU); Worldwide Cancer Research; Instituto de Salud Carlos III; United States Department of Health and Human Services; Unión Europea. European Cooperation in Science and Technology (COST); European Science Foundation (ESF); Department of Technology, Norwegian University of Science and Technology; Asociación Española Contra el CáncerChronic inflammation increases the risk of developing one of several types of cancer. Inflammatory responses are currently thought to be controlled by mechanisms that rely on transcriptional networks that are distinct from those involved in cell differentiation. The orphan nuclear receptor NR5A2 participates in a wide variety of processes, including cholesterol and glucose metabolism in the liver, resolution of endoplasmic reticulum stress, intestinal glucocorticoid production, pancreatic development and acinar differentiation. In genome-wide association studies, single nucleotide polymorphisms in the vicinity of NR5A2 have previously been associated with the risk of pancreatic adenocarcinoma. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration and cooperates with mutant Kras in tumour progression. Here, using a global transcriptomic analysis, we describe an epithelial-cell-autonomous basal pre-inflammatory state in the pancreas of Nr5a2+/- mice that is reminiscent of the early stages of pancreatitis-induced inflammation and is conserved in histologically normal human pancreases with reduced expression of NR5A2 mRNA. In Nr5a2+/-mice, NR5A2 undergoes a marked transcriptional switch, relocating from differentiation-specific to inflammatory genes and thereby promoting gene transcription that is dependent on the AP-1 transcription factor. Pancreatic deletion of Jun rescues the pre-inflammatory phenotype, as well as binding of NR5A2 to inflammatory gene promoters and the defective regenerative response to damage. These findings support the notion that, in the pancreas, the transcriptional networks involved in differentiation-specific functions also suppress inflammatory programmes. Under conditions of genetic or environmental constraint, these networks can be subverted to foster inflammation.