Browsing by Author "Rosa, Lorena"

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    A Novel Gemcitabine-Resistant Gallbladder Cancer Model Provides Insights into Molecular Changes Occurring during Acquired Resistance
    (2023) Vergara-Gómez, Luis; Bizama, Carolina; Zhong, Jun; Buchegger, Kurt; Suárez Vega, Felipe Ignacio; Rosa, Lorena; Ili, Carmen; Weber, Helga; Obreque, Javiera; Espinoza, Karena; Repetto, Gabriela; Roa, Juan C.; Leal, Pamela; García, PatriciaVergara-Gómez, Luis; Bizama, Carolina; Zhong, Jun; Buchegger, Kurt; Suárez Vega, Felipe Ignacio; Rosa, Lorena; Ili, Carmen; Weber, Helga; Obreque, Javiera; Espinoza, Karena; Repetto, Gabriela; Roa, Juan C.; Leal, Pamela; García, Patricia
    Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but the effectiveness of any regimen is limited and recurrence rates are high. 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.
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    Non-steroidal anti-inflammatory drug use and inflammatory markers associated with gallbladder dysplasia: A case-control analysis within a series of patients undergoing cholecystectomy
    (2024) Rosa, Lorena; Cook, Paz; Pfeiffer, Ruth M.; Kemp, Troy J.; Hildesheim, Allan; Pehlivanoglu, Burcin; Adsay, Volkan; Bellolio, Enrique; Araya, Juan Carlos; Pinto, Ligia; Ferreccio, Catterina; Aguayo, Gloria; Vinuela, Eduardo; Koshiol, Jill
    Inflammation has been associated with the development of gallbladder cancer (GBC). However, little is known about the associations of both, inflammation and the use of non-steroidal anti-inflammatory drugs (NSAIDs), with preneoplastic lesions. We analyzed the association of NSAIDs and gallbladder dysplasia in 82 patients with dysplasia and 1843 patients with gallstones among symptomatic patients from a high-risk population. We also analyzed associations for 33 circulating immune-related proteins in a subsample of all 68 dysplasia cases diagnosed at the time of sample selection and 136 gallstone controls. We calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). Biliary colic was reported among most cases (97.6%) and controls (83.9%). NSAID use was inversely associated with gallbladder dysplasia (OR: 0.48, 95%CI: 0.26-0.83). Comparing the highest versus lowest category of each immune-related protein, eight proteins were inversely associated with dysplasia with sex- and age-adjusted ORs ranging from 0.30 (95%CI: 0.12-0.77) for IL-33 to 0.76 (95%CI: 0.59-0.99) for MIP-1B. Of those, GRO remained associated with dysplasia (OR: 0.64, 95%CI: 0.45-0.91) and BCA-1 was borderline associated (OR: 0.74, 95%CI: 0.54-1.01) after adjusting the logistic regression model for sex, age, and NSAIDs. In conclusion, NSAID users were less likely to have gallbladder dysplasia, suggesting that NSAIDs might be beneficial for symptomatic gallstones patients. The inverse association between immune-related markers and dysplasia requires additional research, ideally in prospective studies with asymptomatic participants, to understand the role of the inflammatory response in the natural history of GBC and to address the biological effect of NSAIDs.