?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=https%3A%2F%2Fdoktori.bibl.u-szeged.hu%2Fid%2Feprint%2F12476%2F&rft.title=Unveiling+chemoresistance+in+pancreatic+cancer%3A+the+role+of+AD-MSC%2C+key+resistance+genes%2C+and+TCDCA-driven+molecular+insights&rft.creator=+Parvaneh+Shahram&rft.subject=03.02.21.04.+R%C3%A1k+%C3%A9s+annak+biol%C3%B3giai+alapja&rft.description=This+thesis+investigates+the+complex+interactions+within+the+tumor+microenvironment+(TME)+of%0D%0Apancreatic+ductal+adenocarcinoma+(PDAC)%2C+focusing+on+the+roles+of+bile+acids%2C+stromal+cells%2C%0D%0Aand+chemotherapeutic+agents+in+tumor+progression+and+chemoresistance.+Pancreatic+ductal%0D%0Aadenocarcinoma+(PDAC)+is+one+of+the+most+aggressive+cancers%2C+characterized+by+late-stage%0D%0Adiagnosis+and+limited+treatment+options.+This+study+provides+a+comprehensive+examination+of%0D%0Athe+potential+interplay+between+adipose-derived+stromal+cells+(AD-MSCs)%2C+bile+acids%2C+and%0D%0Achemotherapeutic+agents+in+tumorigenesis+and+chemotherapy+response+within+PDAC.%0D%0AI.+Bile+Acids+and+PDAC+Progression+Bile+acids%2C+especially+TCDCA%2C+play+a+significant+role+in%0D%0Agastrointestinal+cancers%2C+including+PDAC.+Their+impact+depends+on+factors+like+hydrophobicity%2C%0D%0Atransport+mechanisms%2C+and+organ-specific+signaling+pathways.+Elevated+serum+BA+levels%2C+often%0D%0Alinked+to+obstructive+jaundice+(OJ)%2C+correlate+with+worse+survival+outcomes+in+PDAC+patients.%0D%0ABAs+influence+gene+expression+through+the+FXR%2FNF-%CE%BAB+pathway%2C+enhancing+markers+like%0D%0ACDX2+and+MUC2%2C+which+are+associated+with+tumorigenesis.+Using+RNA+sequencing+on+Capan-%0D%0A1+PDAC+cells%2C+our+study+uncovered+2%2C950+differentially+expressed+genes+(DEGs)+following+24-%0D%0Ahour+TCDCA+treatment.+Among+the+upregulated+genes%2C+DKK-1%2C+SerpinB2%2C+KRT80%2C+FST%2C%0D%0AFGFBP1%2C+and+UPLA+were+identified+as+significant+contributors+to+PDAC+tumorigenesis%2C%0D%0Ametastasis%2C+and+cell+migration.+For+example%2C+DKK-1+emerged+as+a+promising+diagnostic+and%0D%0Aprognostic+biomarker+for+PDAC+due+to+its+strong+association+with+disease+progression+and+poor%0D%0Aprognosis.+Similarly%2C+elevated+KRT80+expression+is+linked+to+increased+proliferation+and%0D%0Ainvasiveness.+UPLA+and+SerpinB2%2C+involved+in+extracellular+matrix+(ECM)+remodelling%2C+further%0D%0Aunderscore+the+role+of+BAs+in+enhancing+PDAC+progression.+These+findings+suggest+that%0D%0Atargeting+BA-driven+pathways+could+provide+novel+therapeutic+strategies.%0D%0AII.+Stromal+Cells+and+Chemoresistance+Adipose-derived+mesenchymal+stromal+cells+(ADMSCs)%0D%0Aare+pivotal+components+of+the+tumor+microenvironment+(TME)%2C+contributing+to+cancer%0D%0Adrug+resistance+through+their+tumor-homing+abilities+and+secretory+profiles.+This+study+explored%0D%0Athe+effects+of+oxaliplatin+(OXP)%2C+5-fluorouracil+(5-FU)+and+gemcitabine+(GEM)+on+AD-MSCs%0D%0Aand+Capan-1+cells.+MTT+assays+revealed+that+while+Capan-1+cells+exhibited+dose-dependent%0D%0Aviability+reductions%2C+AD-MSCs+demonstrated+remarkable+resistance%2C+maintaining+over+90%25%0D%0Aviability+even+at+cytotoxic+drug+concentrations.+This+resistance+likely+stems+from+AD-MSCs%E2%80%99%0D%0Aefficient+DNA+repair+mechanisms+and+low+proliferative+rates.%0D%0A55%0D%0ATranscriptomic+and+Cytokine+Profiling+RNA+sequencing+showed+that+OXP+induced%0D%0Asignificant+transcriptional+changes+in+AD-MSCs%2C+with+over+7%2C000+DEGs%2C+while+5-FU+caused%0D%0Aminimal+impact.+Key+pathways+affected+by+OXP+included+DNA+damage+response%2C+p53-%0D%0Amediated+cell+cycle+arrest%2C+and+cytokine+signaling.+GO+enrichment+analysis+highlighted+the%0D%0Aactivation+of+immune-modulatory+pathways%2C+including+IL6%2FJAK%2FSTAT3+and+hypoxia+signaling%2C%0D%0Awhich+contribute+to+chemoresistance.+In+contrast%2C+5-FU%E2%80%99s+limited+effects+on+AD-MSCs+suggest%0D%0Aits+selective+cytotoxicity+against+cancer+cells.+Protein+array+analysis+revealed+that+OXP-treated%0D%0AAD-MSCs+altered+their+secretome+to+foster+a+pro-tumoral+environment%2C+reducing+proangiogenic%0D%0Afactors+like+VEGF+while+increasing+stress-related+proteins+and+ECM+modulators.%0D%0ANotably%2C+cytokines+such+as+GRO%CE%B1+and+IL-4+were+upregulated+under+OXP%2C+promoting+immune%0D%0Asuppression+and+ECM+remodelling.+Conversely%2C+5-FU-treated+AD-MSCs+showed+reduced%0D%0Ametastatic+potential%2C+with+lower+expression+of+ECM+remodelling+factors+and+chemokines+like%0D%0ASDF-1%CE%B1.+These+results+emphasize+the+differential+impact+of+these+drugs+on+stromal+cell+behavior%0D%0Aand+their+potential+to+shape+the+TME.+Therapeutic+strategies+targeting+AD-MSC-secreted%0D%0Afactors+such+as+GRO%CE%B1%2C+GM-CSF%2C+EMMPRIN%2C+and+IL-4+and+pathways+involved+in+hypoxia%0D%0Asignaling%2C+immune+modulation%2C+and+ECM+remodelling+could+mitigate+the+supportive+role+of%0D%0AAD-MSCs+and+enhance+treatment+efficacy.+Future+research+should+leverage+multi-omics%0D%0Aapproaches+to+dissect+the+precise+roles+of+AD-MSC-derived+factors+in+tumor+progression+and%0D%0Aresistance%2C+aiming+to+develop+innovative+strategies+that+disrupt+stromal-tumor+crosstalk.+This%0D%0Aapproach+holds+promise+for+overcoming+resistance+and+improving+outcomes+in+PDAC+and+other%0D%0Astromal-rich+cancers.+Collectively%2C+these+findings+deepen+our+understanding+of+the+molecular%0D%0Amechanisms+driving+AD-MSC-mediated+chemotherapy+resistance+and+bile+acid-induced+tumor%0D%0Apromotion%2C+paving+the+way+for+targeted+therapies+to+improve+patient+outcomes.%0D%0AIII.+3D+model+of+pancreatic+cancer+We+explored+3D+bioprinting+as+a+method+for+developing%0D%0Aa+3D+model+of+pancreatic+cancer+and+artificial+pancreatic+islets.&rft.date=2025&rft.type=Disszert%C3%A1ci%C3%B3&rft.type=NonPeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=https%3A%2F%2Fdoktori.bibl.u-szeged.hu%2Fid%2Feprint%2F12476%2F2%2FShahram%2520Parvaneh_PhDThesis_booklet.pdf&rft.format=application%2Fpdf&rft.language=en&rft.identifier=https%3A%2F%2Fdoktori.bibl.u-szeged.hu%2Fid%2Feprint%2F12476%2F13%2FShahram%2520Parvaneh_PhDThesis_Final.pdf&rft.format=application%2Fpdf&rft.language=en&rft.identifier=https%3A%2F%2Fdoktori.bibl.u-szeged.hu%2Fid%2Feprint%2F12476%2F15%2FJournal%2520of%2520Biotechnology.pdf&rft.format=application%2Fpdf&rft.language=en&rft.identifier=https%3A%2F%2Fdoktori.bibl.u-szeged.hu%2Fid%2Feprint%2F12476%2F16%2FChemoresistance%2520in%2520Pancreatic%2520Cancer.pdf&rft.format=application%2Fpdf&rft.language=en&rft.identifier=https%3A%2F%2Fdoktori.bibl.u-szeged.hu%2Fid%2Feprint%2F12476%2F17%2FThree-dimensional%2520bioprinting%2520of%2520functional.pdf&rft.identifier=+++Parvaneh+Shahram%0A+++Unveiling+chemoresistance+in+pancreatic+cancer%3A+the+role+of+AD-MSC%2C+key+resistance+genes%2C+and+TCDCA-driven+molecular+insights.%0A++Doktori+%C3%A9rtekez%C3%A9s%2C+Szegedi+Tudom%C3%A1nyegyetem+(2000-).+%0A(2025)+++++&rft.language=eng