2022
Dysregulation of the Scribble/YAP/β‐catenin axis sustains the fibroinflammatory response in a PKHD1−/− mouse model of congenital hepatic fibrosis
Fabris L, Milani C, Fiorotto R, Mariotti V, Kaffe E, Seller B, Sonzogni A, Strazzabosco M, Cadamuro M. Dysregulation of the Scribble/YAP/β‐catenin axis sustains the fibroinflammatory response in a PKHD1−/− mouse model of congenital hepatic fibrosis. The FASEB Journal 2022, 36: e22364. PMID: 35593740, PMCID: PMC9150862, DOI: 10.1096/fj.202101924r.Peer-Reviewed Original ResearchConceptsYes-associated proteinPlanar cell polarityΒ-cateninΒ-catenin axisYAP nuclear importRole of ScribbleNuclear translocationYAP/TAZΒ-catenin signalingCell polarityNuclear importCyst cellsNuclear expressionScribble expressionΒ-catenin nuclear expressionConditional deletionGenetic defectsTissue growth factor expressionIntegrin β6Connective tissue growth factor expressionCyst growthExpressionCystic cholangiocytesMRNA levelsScribbles
2020
IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression
Stein S, Henze L, Poch T, Carambia A, Krech T, Preti M, Schuran FA, Reich M, Keitel V, Fiorotto R, Strazzabosco M, Fischer L, Li J, Müller LM, Wagner J, Gagliani N, Herkel J, Schwinge D, Schramm C. IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression. Journal Of Hepatology 2020, 74: 919-930. PMID: 33197512, PMCID: PMC8778963, DOI: 10.1016/j.jhep.2020.10.035.Peer-Reviewed Original ResearchConceptsIL-17A/FIL-17PD-L1T cellsOT-1Mouse modelAutoimmune cholestatic liver diseaseCell death ligand 1Cholangiocyte organoidsMajor histocompatibility complex IBile duct inflammationAntigen-specific CD8Bile duct injuryPD-L1 expressionDeath ligand 1Driver of inflammationTreatment of cholangitisCholestatic liver diseaseResponse of miceImportant protective effectDuct inflammationExperimental cholangitisDuct injuryAdoptive transferCytotoxic CD8
2019
The tumour microenvironment and immune milieu of cholangiocarcinoma
Fabris L, Perugorria M, Mertens J, Björkström NK, Cramer T, Lleo A, Solinas A, Sänger H, Lukacs‐Kornek V, Moncsek A, Siebenhüner A, Strazzabosco M. The tumour microenvironment and immune milieu of cholangiocarcinoma. Liver International 2019, 39: 63-78. PMID: 30907492, PMCID: PMC10878127, DOI: 10.1111/liv.14098.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAnimalsBile Duct NeoplasmsCholangiocarcinomaDisease Models, AnimalEndothelial CellsFibroblastsHumansImmunity, InnateTumor MicroenvironmentConceptsTumor microenvironmentAbundant desmoplastic reactionCancer-associated fibroblastsHigh mortality rateTumor-promoting functionsEpithelial cancer cellsImmune milieuImmune cellsPancreatic cancerEffective therapyDesmoplastic reactionMortality rateCholangiocarcinomaInvasive abilityTherapeutic gainStromal cellsTumor cellsEndothelial cellsEpithelial counterpartsCancer cellsIntrahepatic variantCellular populationsMicroenvironmentCellsRecent studies
2018
Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma
Cadamuro M, Brivio S, Mertens J, Vismara M, Moncsek A, Milani C, Fingas C, Cristina Malerba M, Nardo G, Dall'Olmo L, Milani E, Mariotti V, Stecca T, Massani M, Spirli C, Fiorotto R, Indraccolo S, Strazzabosco M, Fabris L. Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma. Journal Of Hepatology 2018, 70: 700-709. PMID: 30553841, PMCID: PMC10878126, DOI: 10.1016/j.jhep.2018.12.004.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBile Duct NeoplasmsCancer-Associated FibroblastsCell Line, TumorCholangiocarcinomaDisease Models, AnimalEndothelial CellsHeterograftsHumansImatinib MesylateLiverLymphangiogenesisLymphokinesMaleMiceMice, SCIDMyofibroblastsPlatelet-Derived Growth FactorProtein Kinase InhibitorsRatsRats, Inbred F344Receptor, Platelet-Derived Growth Factor betaVascular Endothelial Growth Factor AVascular Endothelial Growth Factor CConceptsCancer-associated fibroblastsLymphatic endothelial cellsCholangiocarcinoma specimensMetastatic spreadStromal reactionLiver myofibroblastsGrowth factorExtensive stromal reactionLymph node metastasisEarly metastatic spreadLevels of VEGFBH3 mimetic navitoclaxPlatelet-derived growth factorRole of PDGFVascular growth factorsTumor-associated lymphangiogenesisVEGF-C secretionTransendothelial electric resistanceCholangiocarcinoma invasivenessHuman lymphatic endothelial cellsCurative therapyNode metastasisBiliary treeEarly metastasisPDGFRβ inhibitorAnimal models of cholestasis: An update on inflammatory cholangiopathies
Mariotti V, Cadamuro M, Spirli C, Fiorotto R, Strazzabosco M, Fabris L. Animal models of cholestasis: An update on inflammatory cholangiopathies. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2018, 1865: 954-964. PMID: 30398152, DOI: 10.1016/j.bbadis.2018.07.025.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsAnimal modelsPro-fibrotic signalsChronic liver diseasePrimary biliary cholangitisBile duct ligationFrequent clinical conditionBiliary injuryBiliary cholangitisBiliary obstructionLiver diseaseBiliary epitheliumDuct ligationInflammatory cholangiopathyAdaptive immunityClinical conditionsControversial diseasePathogenetic sequenceCholangiopathyCholestasisExperimental modelCholangitisDiseasePrimary targetChemical inductionCell elementsAnimal models for cystic fibrosis liver disease (CFLD)
Fiorotto R, Amenduni M, Mariotti V, Cadamuro M, Fabris L, Spirli C, Strazzabosco M. Animal models for cystic fibrosis liver disease (CFLD). Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2018, 1865: 965-969. PMID: 30071276, PMCID: PMC6474816, DOI: 10.1016/j.bbadis.2018.07.026.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAnimalsCystic FibrosisDisease Models, AnimalGastrointestinal MicrobiomeGene EditingGenetic TherapyHumansImmunity, InnateLiver DiseasesConceptsCystic fibrosis liver diseaseLiver diseaseAnimal modelsCF animal modelsCystic fibrosisEpithelial innate immunityMore specific treatmentsNovel therapeutic treatmentsDifferent animal modelsLiver manifestationsSevere complicationsPathogenetic factorSpecific treatmentCF miceGut microbiotaInnate immunityTherapeutic treatmentLiver phenotypeDiseaseChloride channelsCystic fibrosis transmembrane conductance regulator (CFTR) channelCFTR expressionHuman diseasesTreatmentApical membraneAnimal models of cholangiocarcinoma: What they teach us about the human disease
Cadamuro M, Brivio S, Stecca T, Kaffe E, Mariotti V, Milani C, Fiorotto R, Spirli C, Strazzabosco M, Fabris L. Animal models of cholangiocarcinoma: What they teach us about the human disease. Clinics And Research In Hepatology And Gastroenterology 2018, 42: 403-415. PMID: 29753731, DOI: 10.1016/j.clinre.2018.04.008.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsAnimal modelsNovel therapeutic approachesRelevant animal modelsPathogenesis of cholangiocarcinomaBiliary carcinogenesisTreatment optionsTherapeutic approachesRodent modelsLethal cancersClinical phenotypeExperimental modelCholangiocarcinomaAggressive behaviorCell interactionsHuman diseasesComplex cell biologyMultiple cell interactionsMolecular perturbationsPathogenesisTumorsCancerDiseaseCarcinogenesisβ‐Catenin and interleukin‐1β–dependent chemokine (C‐X‐C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis
Kaffe E, Fiorotto R, Pellegrino F, Mariotti V, Amenduni M, Cadamuro M, Fabris L, Strazzabosco M, Spirli C. β‐Catenin and interleukin‐1β–dependent chemokine (C‐X‐C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis. Hepatology 2018, 67: 1903-1919. PMID: 29140564, PMCID: PMC5906178, DOI: 10.1002/hep.29652.Peer-Reviewed Original ResearchConceptsSignal transducerΒ-cateninJanus kinase/signal transducerKinase/signal transducerActivator of transcriptionProtein kinase ATranscription 3 (STAT3) phosphorylationHepatic disease 1 (PKHD1) geneNOD-like receptorsKinase ATranscription 3Novel therapeutic avenuesGenetic diseasesNuclear translocationCognate receptorsFamily 3Nuclear factorMouse modelPKHD1Activated B cellsPhosphorylationActivatorCyst growthTherapeutic avenuesAMG 487
2017
The deleterious interplay between tumor epithelia and stroma in cholangiocarcinoma
Cadamuro M, Stecca T, Brivio S, Mariotti V, Fiorotto R, Spirli C, Strazzabosco M, Fabris L. The deleterious interplay between tumor epithelia and stroma in cholangiocarcinoma. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2017, 1864: 1435-1443. PMID: 28757170, PMCID: PMC6386155, DOI: 10.1016/j.bbadis.2017.07.028.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsTumor reactive stromaReactive stromaMain cellular componentsDeleterious interplayCyto/chemokinesCellular componentsParacrine signalsPrognosis of cholangiocarcinomaTumor epithelial cellsCell interactionsEarly invasivenessJesus BanalesMarco MarzioniNicholas LaRussoPeter JansenDifferent cell elementsEpithelial cellsEpithelial malignanciesTumor behaviorTumor epitheliumGrowth factorNeoplastic cellsTumor progressionCentral roleStromal componentsPathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium
Strazzabosco M, Fiorotto R, Cadamuro M, Spirli C, Mariotti V, Kaffe E, Scirpo R, Fabris L. Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2017, 1864: 1374-1379. PMID: 28754453, PMCID: PMC5785585, DOI: 10.1016/j.bbadis.2017.07.023.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsToll-like receptorsLiver damageCystic fibrosis-related liver diseaseInnate immunityDamage-associated molecular patternsEpithelial innate immunityPro-inflammatory behaviorBiliary epithelial cellsNumber of receptorsJesus BanalesMarco MarzioniNicholas LaRussoPeter JansenLiver injuryLiver diseaseBile flowInflammatory processBiliary epitheliumInflammatory responsePathophysiologic implicationsReparative processesNumber of evidencesFirst defense lineCholangiocytesMolecular patternsAnimal models of biliary injury and altered bile acid metabolism
Mariotti V, Strazzabosco M, Fabris L, Calvisi DF. Animal models of biliary injury and altered bile acid metabolism. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2017, 1864: 1254-1261. PMID: 28709963, PMCID: PMC5764833, DOI: 10.1016/j.bbadis.2017.06.027.Peer-Reviewed Original ResearchConceptsBile acid metabolismBiliary injuryMouse modelAnimal modelsDistinct immune systemCholestatic liver injuryAcid metabolismJesus BanalesMarco MarzioniNicholas LaRussoPeter JansenBiliary repairLiver injuryDuctular reactionLiver repairObstructive cholestasisDisease progressionPeribiliary inflammationMain phenotypic featuresBiliary dysgenesisViral infectionImmune systemLiver homeostasisLiver phenotypeHuman setting
2016
Adenylyl cyclase 5 links changes in calcium homeostasis to cAMP-dependent cyst growth in polycystic liver disease
Spirli C, Mariotti V, Villani A, Fabris L, Fiorotto R, Strazzabosco M. Adenylyl cyclase 5 links changes in calcium homeostasis to cAMP-dependent cyst growth in polycystic liver disease. Journal Of Hepatology 2016, 66: 571-580. PMID: 27826057, PMCID: PMC5316496, DOI: 10.1016/j.jhep.2016.10.032.Peer-Reviewed Original ResearchMeSH KeywordsAdenylyl Cyclase InhibitorsAdenylyl CyclasesAnimalsCalciumCell ProliferationCyclic AMPCystsDisease Models, AnimalHomeostasisHumansLiver DiseasesMAP Kinase Signaling SystemMiceMice, KnockoutPolycystic Kidney, Autosomal DominantRNA InterferenceSignal TransductionStromal Interaction Molecule 1TRPP Cation ChannelsVascular Endothelial Growth Factor AConceptsProgressive cyst growthPolycystic liver diseaseNovel therapeutic targetLiver diseaseKO miceCyst growthTherapeutic targetBiliary organoidsDouble conditional knockout miceCAMP productionAutosomal dominant polycystic kidney diseaseVascular endothelial growth factorCell proliferationDominant polycystic kidney diseaseEndothelial growth factorConditional knockout micePolycystic kidney diseaseLiver transplantationLevels of cAMPStore-operated CaCystic areasKidney diseaseCyst sizeVivo treatmentKnockout miceMacrophage recruitment by fibrocystin‐defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis
Locatelli L, Cadamuro M, Spirlì C, Fiorotto R, Lecchi S, Morell C, Popov Y, Scirpo R, De Matteis M, Amenduni M, Pietrobattista A, Torre G, Schuppan D, Fabris L, Strazzabosco M. Macrophage recruitment by fibrocystin‐defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis. Hepatology 2016, 63: 965-982. PMID: 26645994, PMCID: PMC4764460, DOI: 10.1002/hep.28382.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, NeoplasmChemokinesClodronic AcidCollagenDisease Models, AnimalEpithelial CellsGenetic Diseases, InbornIntegrinsLiver CirrhosisMacrophagesMiceMyofibroblastsReceptors, Cell SurfaceSnail Family Transcription FactorsTranscription FactorsTransforming Growth Factor beta1Tumor Necrosis Factor-alphaConceptsCongenital hepatic fibrosisMacrophage recruitmentPortal hypertensionPortal fibrosisHepatic fibrosisLiver fibrosisCell dysfunctionBile duct changesRange of chemokinesLow-grade inflammationProgressive liver fibrosisDuctal plate malformationEpithelial cell dysfunctionGrowth factor-β1Biliary epithelial cellsBiliary fibrosisLiver failureMacrophage infiltratesLiver cystsDuct changesProinflammatory cytokinesPeribiliary fibrosisBiliary epitheliumDisease progressionM1 phenotype
2014
Characterization of animal models for primary sclerosing cholangitis (PSC)
Fickert P, Pollheimer MJ, Beuers U, Lackner C, Hirschfield G, Housset C, Keitel V, Schramm C, Marschall HU, Karlsen TH, Melum E, Kaser A, Eksteen B, Strazzabosco M, Manns M, Trauner M, Group I. Characterization of animal models for primary sclerosing cholangitis (PSC). Journal Of Hepatology 2014, 60: 1290-1303. PMID: 24560657, PMCID: PMC4517670, DOI: 10.1016/j.jhep.2014.02.006.Peer-Reviewed Original ResearchConceptsPrimary sclerosing cholangitisAnimal modelsEnd-stage liver diseaseStage liver diseaseDevelopment of cholestasisNew treatment strategiesEffective medical treatmentLiver transplantationSclerosing cholangitisBiliary fibrosisChronic cholangiopathiesLiver diseaseTreatment strategiesStudy groupHigh riskPathogenetic conceptsMedical treatmentFrequent needCholangitisCholangiopathyCholestasisPoor understandingTransplantationFibrosisGroup
2013
Protein kinase a‐dependent pSer675‐β‐catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis
Spirli C, Locatelli L, Morell CM, Fiorotto R, Morton SD, Cadamuro M, Fabris L, Strazzabosco M. Protein kinase a‐dependent pSer675‐β‐catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis. Hepatology 2013, 58: 1713-1723. PMID: 23744610, PMCID: PMC3800498, DOI: 10.1002/hep.26554.Peer-Reviewed Original ResearchConceptsAutosomal recessive polycystic kidney diseaseCongenital hepatic fibrosisCaroli's diseaseΒ-cateninHepatic fibrosisRac-1 inhibitionIntrahepatic bile ductsRecessive polycystic kidney diseasePotential therapeutic targetPolycystic kidney diseaseStimulation of cAMPRac-1 activityE-cadherin expressionBile ductKidney diseaseLiver pathologyCystic dysplasiaMouse modelTherapeutic targetTranscriptional activityNuclear translocationDiseasePKA blockerCholangiocytesFibrosis
2011
Dual farnesoid X receptor/TGR5 agonist INT‐767 reduces liver injury in the Mdr2−/− (Abcb4−/−) mouse cholangiopathy model by promoting biliary HCO output
Baghdasaryan A, Claudel T, Gumhold J, Silbert D, Adorini L, Roda A, Vecchiotti S, Gonzalez FJ, Schoonjans K, Strazzabosco M, Fickert P, Trauner M. Dual farnesoid X receptor/TGR5 agonist INT‐767 reduces liver injury in the Mdr2−/− (Abcb4−/−) mouse cholangiopathy model by promoting biliary HCO output. Hepatology 2011, 54: 1303-1312. PMID: 22006858, PMCID: PMC3744065, DOI: 10.1002/hep.24537.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphatasesAnalysis of VarianceAnimalsAnion Transport ProteinsATP Binding Cassette Transporter, Subfamily BBile Acids and SaltsBiliary Tract DiseasesCholic AcidsDisease Models, AnimalLiver DiseasesMaleMiceMice, Inbred C57BLRandom AllocationReceptors, Cytoplasmic and NuclearReceptors, G-Protein-CoupledStatistics, NonparametricConceptsFarnesoid X receptorINT-767Liver injuryChronic cholangiopathiesTGR5 agonistsINT-747Hepatic inflammationINT-777Bile secretionBiliary bile acid outputActivation of FXRNuclear farnesoid X receptorSerum liver enzymesBile acid outputBile acid homeostasisFXR-dependent mannerBile acid synthesisMembrane G protein-coupled receptorsG protein-coupled receptorsLiver transplantationProtein-coupled receptorsBiliary fibrosisAcid outputChow dietTherapeutic optionsLoss of CFTR Affects Biliary Epithelium Innate Immunity and Causes TLR4–NF-κB—Mediated Inflammatory Response in Mice
Fiorotto R, Scirpo R, Trauner M, Fabris L, Hoque R, Spirli C, Strazzabosco M. Loss of CFTR Affects Biliary Epithelium Innate Immunity and Causes TLR4–NF-κB—Mediated Inflammatory Response in Mice. Gastroenterology 2011, 141: 1498-1508.e5. PMID: 21712022, PMCID: PMC3186841, DOI: 10.1053/j.gastro.2011.06.052.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnti-Bacterial AgentsBile DuctsCholagogues and CholereticsCholangitisColitisCytokinesDextran SulfateDisease Models, AnimalEpithelial CellsHEK293 CellsHumansImmunity, InnateInflammation MediatorsKeratin-19Leukocyte Common AntigensLipopolysaccharidesMiceMice, Inbred C57BLMice, Inbred CFTRMice, KnockoutNeomycinNF-kappa BPhosphorylationPolymyxin BSrc-Family KinasesTime FactorsToll-Like Receptor 4TransfectionUrsodeoxycholic AcidConceptsCFTR KO miceBiliary epitheliumCystic fibrosisPortal inflammationBiliary damageInflammatory responseInnate immunityGut-derived bacterial productsTLR4 inhibitor TAK-242Toll-like receptor 4Cystic fibrosis transmembrane conductance regulatorInhibitor TAK-242Wild-type littermatesActivation of NFNuclear factor κBOral neomycinTLR4-NFTAK-242Liver damagePathogenetic roleBile flowDuctular reactionReceptor 4Cytokine secretionUrsodeoxycholic acid
2009
Mammalian target of rapamycin regulates vascular endothelial growth factor–dependent liver cyst growth in polycystin‐2–defective mice
Spirli C, Okolicsanyi S, Fiorotto R, Fabris L, Cadamuro M, Lecchi S, Tian X, Somlo S, Strazzabosco M. Mammalian target of rapamycin regulates vascular endothelial growth factor–dependent liver cyst growth in polycystin‐2–defective mice. Hepatology 2009, 51: 1778-1788. PMID: 20131403, PMCID: PMC2930014, DOI: 10.1002/hep.23511.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCystsDisease Models, AnimalExtracellular Signal-Regulated MAP KinasesHypoxia-Inducible Factor 1, alpha SubunitInsulin-Like Growth Factor IIntracellular Signaling Peptides and ProteinsLiver DiseasesMicePolycystic Kidney, Autosomal DominantProtein Serine-Threonine KinasesSirolimusTOR Serine-Threonine KinasesTRPP Cation ChannelsVascular Endothelial Growth Factor AConceptsMammalian targetInsulin-like growth factor-1Extracellular signal-regulated kinase 1/2Extracellular signal-regulated kinaseSignal-regulated kinase 1/2Autosomal dominant polycystic kidney diseaseLiver cyst growthVascular endothelial growth factorProtein kinase AInsulin-like growth factor 1 receptorSignal-regulated kinaseGrowth factor 1 receptorVEGF secretionCyst growthMTOR inhibitor rapamycinFactor 1 receptorHIF1alpha accumulationFactor 1 alphaDependent phosphorylationKinase AKinase 1/2P-P70S6KInhibitor rapamycinHypoxia-inducible factor-1 alphaExpression of CC3