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Here, we investigated the molecular mechanisms of acquired resistance in GBC through the development and characterization of two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR). Morphological changes, cross-resistance, and migratory\/invasive capabilities were evaluated. Then, microarray-based transcriptome profiling and quantitative SILAC-based phosphotyrosine proteomic analyses were performed to identify biological processes and signaling pathways dysregulated in gemcitabine-resistant GBC cells. The transcriptome profiling of parental and gemcitabine-resistant cells revealed the dysregulation of protein-coding genes that promote the enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, the phosphoproteomics analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as ABL1, PDGFRA, and LYN, which could be novel therapeutic targets in GBC. Accordingly, NOZ GemR showed increased sensitivity toward the multikinase inhibitor dasatinib compared to parental cells. Our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant GBC cells, which greatly expands our understanding of the underlying mechanisms of acquired drug resistance in GBC.<\/jats:p>","DOI":"10.3390\/ijms24087238","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T02:28:12Z","timestamp":1681439292000},"page":"7238","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Novel Gemcitabine-Resistant Gallbladder Cancer Model Provides Insights into Molecular Changes Occurring during Acquired Resistance"],"prefix":"10.3390","volume":"24","author":[{"given":"Luis","family":"Vergara-G\u00f3mez","sequence":"first","affiliation":[{"name":"Biomedicine and Translational Research Laboratory, Centre of Excellence in Translational Medicine and Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Temuco 4810296, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Bizama","sequence":"additional","affiliation":[{"name":"School of Medicine, Department of Pathology, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8330024, Chile"},{"name":"Center for Cancer Prevention and Control (CECAN), Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3148-4143","authenticated-orcid":false,"given":"Jun","family":"Zhong","sequence":"additional","affiliation":[{"name":"Delta Omics Biotechnology, Rockville, MD 20855, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt","family":"Buchegger","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Universidad de La Frontera, Temuco 4810296, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Su\u00e1rez","sequence":"additional","affiliation":[{"name":"School of Medicine, Department of Pathology, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8330024, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Rosa","sequence":"additional","affiliation":[{"name":"School of Medicine, Department of Pathology, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8330024, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4009-4406","authenticated-orcid":false,"given":"Carmen","family":"Ili","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Biology (LIBi), Centre of Excellence in Translational Medicine and Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Temuco 4810296, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helga","family":"Weber","sequence":"additional","affiliation":[{"name":"Biomedicine and Translational Research Laboratory, Centre of Excellence in Translational Medicine and Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Temuco 4810296, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javiera","family":"Obreque","sequence":"additional","affiliation":[{"name":"School of Medicine, Department of Pathology, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8330024, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karena","family":"Espinoza","sequence":"additional","affiliation":[{"name":"Center for Genetics and Genomics, Facultad de Medicina, Cl\u00ednica Alemana, Universidad del Desarrollo, Santiago 7610658, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0120-5684","authenticated-orcid":false,"given":"Gabriela","family":"Repetto","sequence":"additional","affiliation":[{"name":"Center for Genetics and Genomics, Facultad de Medicina, Cl\u00ednica Alemana, Universidad del Desarrollo, Santiago 7610658, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8313-8774","authenticated-orcid":false,"given":"Juan C.","family":"Roa","sequence":"additional","affiliation":[{"name":"School of Medicine, Department of Pathology, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8330024, Chile"},{"name":"Center for Cancer Prevention and Control (CECAN), Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"},{"name":"Millennium Institute on Immunology and Immunotherapy (IMII), Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Leal","sequence":"additional","affiliation":[{"name":"Biomedicine and Translational Research Laboratory, Centre of Excellence in Translational Medicine and Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Temuco 4810296, Chile"},{"name":"Department of Agricultural Sciences and Natural Resources, Faculty of Agricultural and Forestry Science, Universidad de La Frontera, Temuco 4810296, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3817-4896","authenticated-orcid":false,"given":"Patricia","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"School of Medicine, Department of Pathology, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8330024, Chile"},{"name":"Center for Cancer Prevention and Control (CECAN), Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41572-022-00398-y","article-title":"Gallbladder cancer","volume":"8","author":"Roa","year":"2022","journal-title":"Nat. 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