Browsing by Author "Bizama, Carolina"

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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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    Advances towards the use of gastrointestinal tumor patient-derived organoids as a therapeutic decision-making tool
    (2023) Obreque Castro, Javiera Constanza; Vergara Gómez, Luis; Venegas Labra, Nicolás; Weber, Helga; Owen, Gareth Ivor; Pérez Moreno, Pablo; Leal, Pamela; Roa Strauch, Juan Carlos Enrique; Bizama, Carolina
    In December 2022 the US Food and Drug Administration (FDA) removed the requirement that drugs in development must undergo animal testing before clinical evaluation, a declaration that now demands the establishment and verification of ex vivo preclinical models that closely represent tumor complexity and that can predict therapeutic response. Fortunately, the emergence of patient-derived organoid (PDOs) culture has enabled the ex vivo mimicking of the pathophysiology of human tumors with the reassembly of tissue-specific features. These features include histopathological variability, molecular expression profiles, genetic and cellular heterogeneity of parental tissue, and furthermore growing evidence suggests the ability to predict patient therapeutic response. Concentrating on the highly lethal and heterogeneous gastrointestinal (GI) tumors, herein we present the state-of-the-art and the current methodology of PDOs. We highlight the potential additions, improvements and testing required to allow the ex vivo of study the tumor microenvironment, as well as offering commentary on the predictive value of clinical response to treatments such as chemotherapy and immunotherapy.
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    Correction to : MicroRNA‑335‑5p is a potential suppressor of metastasis and invasion in gastric cancer
    (2021) Sandoval Bórquez, Alejandra; Polakovicova, Iva; Carrasco Véliz, Nicolás; Lobos González, Lorena; Riquelme, Ismael; Carrasco Avino, Gonzalo; Bizama, Carolina; Norero Muñoz, Enrique; Owen, Gareth Ivor; Roa Strauch, Juan Carlos Enrique; Corvalán R., Alejandro
    An amendment to this paper has been published and can be accessed via the original article.
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    Evaluación de la respuesta inmune anti-tumoral mediada por linfocitos T en organoides derivados de pacientes con cáncer de vesícula biliar
    (2024) Obreque Castro, Javiera Constanza; Bizama, Carolina; Roa, Juan Carlos; Montecinos Acuña, Viviana; Pontificia Universidad Católica de Chile. Escuela de Medicina
    El cáncer de vesícula biliar (GBC) es una de las neoplasias más comunes y agresivas dentro del tracto biliar. Particularmente en nuestro país, el GBC se ha reportado como un problema de salud pública, especialmente en mujeres donde contribuye como la quinta causa de muerte por cáncer. Actualmente, el único tratamiento efectivo es la resección quirúrgica de la vesícula en estadios temprano. Sin embargo, la mayoría de los pacientes son diagnosticados en estadios avanzados, donde la única alternativa terapéutica es la quimioterapia con gemcitabina y cisplatino, la cual presenta muy baja respuesta. Es por esto, que la búsqueda de nuevos blancos de terapia y de modelos preclínicos que representen fielmente la respuesta a terapias ha cobrado gran interés en la investigación biomédica con enfoques en medicina personalizada. En los tumores de GBC se ha descrito la presencia de las células iniciadoras de tumor (TICs) o cancer stem cells (CSC), caracterizadas por la expresión doble positiva de los marcadores CD44 y CD133. Una de las características de las TICs, es la evasión de la respuesta inmune antitumoral, a través, de la expresión de los immune checkpoint (o puntos de control inmune) desencadenando la supresión de los linfocitos T citotóxicos, encargados de orquestar la respuesta inmune antitumoral. En los últimos años, la inmunoterapia ha revolucionado el tratamiento del cáncer y actualmente se utiliza con resultados favorables en el tratamiento de diferentes tipos de tumores. Dentro de las inmunoterapias aprobadas por la FDA, se encuentran los inhibidores de los inmune checkpoint, PD-L1/PD-1, CTLA4 y LAG-3. Inicialmente estas terapias fueron aprobados para su uso en melanoma, pero en la actualidad los dos primeros se utilizan en variados tipos de cáncer incluido el gástrico. Por lo tanto, para el análisis de la respuesta y predicción a estas nuevas inmunoterapias se requiere de nuevos modelos in vitro de cáncer, que sean capaces de recapitular la interacción de las células del cáncer con el componente inmune. Dentro de estos modelos, se propone el uso de los cultivos 3D de organoides tumorales derivados de pacientes (PDOs) como una poderosa herramienta que imita las características histológicas, genéticas y fisiopatológicas del tumor del cual derivan. Sin embargo, el principal desafío es enriquecer este modelo de PDOs tumorales con células del componente inmune para poder estudiar la respuesta de los pacientes a la inmunoterapia. Actualmente, el uso de co-cultivo entre organoides y células inmunes, se ha utilizado para generar linfocitos TCD8 reactivos y evaluar la capacidad citotóxica TCD8 en contra de las células tumorales. Tomando todo esto en consideración, el presente proyecto de tesis tuvo como hipótesis: “La interacción directa entre organoides derivados de pacientes con cáncer de vesícula biliar y células inmunes, permite evaluar la respuesta antitumoral mediada por linfocitos T y el efecto de inhibidores de PD-1”.
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    Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia
    (2020) Rosa, L.; Muñoz Durango, Natalia; García Cañete, Patricia; Bizama, Carolina; González Briones, Ximena María; Wichmann Pérez, Ignacio Alberto; Arrese, Marco; Ferreccio Readi, Catterina; Kalergis Parra, Alexis Mikes; Miquel P., Juan Francisco; Roa Strauch, Juan Carlos Enrique; Lobos-Gonzalez, L.; Gomez, N.; Saavedra, N.; Guevara, F.; Villegas, J.; Espinoza, J. A.
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    Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor.
    (2020) García Cañete, Patricia; Bizama, Carolina; Rosa, Lorena.; Cerda Infante, Javier; Sánchez, Marianela.; Montecinos Acuña, Viviana; Alfaro, Francisca.; Leiva-Acevedo, Claudia.; Romero, Diego.; Kato Cardemil, Sumie Rode
    Abstract Background Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry. Results After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. Conclusions The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.
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    Hippo-YAP1 Is a Prognosis Marker and Potentially Targetable Pathway in Advanced Gallbladder Cancer
    (2020) García Muñoz, Patricia; Rosa, L.; Vargas, S.; Weber, H.; Espinoza, J. A.; Suárez, F.; Nervi Nattero, Bruno; Obreque Castro, Javiera Constanza; Roa Strauch, Juan Carlos Enrique; Bizama, Carolina; Romero Calvo, I.; Elgueta, N.; Rivera, V.; Leal, P.; Viñuela, E.; Aguayo, G.; Muniz, S.; Sagredo, A.
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    IL-8, GRO and MCP-1 produced by hepatocellular carcinoma microenvironment determine the migratory capacity of human bone marrow-derived mesenchymal stromal cells without affecting tumor aggressiveness
    (2017) Bayo, J.; Real, A.; Fiore, E.; Malvicini, M.; Sganga, L.; Bolontrade, M.; Andriani, O.; Bizama, Carolina; Fresno, C.; Podhajcer, O.; Fernandez, E.; Gidekel, M.; Mazzolini, G.; Garcia, M.
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    Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate
    (2020) Pandey, A.; Stawiski, E. W.; Durinck, S.; Gowda, H.; Goldstein, L. D.; Barbhuiya, M. A.; Schroder, M. S.; Sreenivasamurthy, S. K.; Bizama, Carolina; Roa Strauch, Juan Carlos Enrique; Kim, S. W.; Phalke, S.; Suryamohan, K.; Lee, K.; Chakraborty, P.; Kode, V.; Shi, X. S.; Chatterjee, A.; Datta, K.; Khan, A. A.; Subbannayya, T.; Wang, J.; Chaudhuri, S.; Gupta, S.; Shrivastav, B. R.; Jaiswal, B. S.; Poojary, S. S.; Bhunia, S.; García, P.; Rosa, L.; Kwon, W.; Kim, H.; Han, Y.; Yadav, T. D.; Ramprasad, V. L.; Chaudhuri, A.; Modrusan, Z.; Tiwari, P. K.; Jang, J. Y.; Seshagiri, S.
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    Low expression of equilibrative nucleoside transporter 1 is associated with poor prognosis in chemotherapy-naive pT2 gallbladder adenocarcinoma patients
    (2016) Espinoza, J. A.; García Muñoz, Patricia; Bizama, Carolina; Leal, J. L.; Riquelme, I.; Weber, H.; Macanas Pirard, Patricia; Aguayo Bonniard, Gloria Alejandra; Viñuela Fawaz, Eduardo Andrés; Roa Strauch, Juan Carlos Enrique; Nervi, B.
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    miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in gastric cancer through regulation of the PI3K/AKT/mTOR pathway
    (2016) Riquelme, I.; Tapia, O.; Leal, P.; Sandoval, A.; Varga, M.; Letelier, P.; Buchegger, K.; Bizama, Carolina; Espinoza, J.; Peek, R.; Araya, J.; Roa Strauch, Juan Carlos Enrique
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    Mucin 5B, carbonic anhydrase 9 and claudin 18 are potential theranostic markers of gallbladder carcinoma
    (2019) Espinoza, J.A.; Riquelme, I.; Sagredo, E.A.; Rosa, L.; Garcia, P.; Bizama, Carolina; Apud-Bell, M.; Leal, P.; Weber, H.; Benavente, F.; Vargas, S.; Romero, D.; Kalergis Parra, Alexis Mikes; Roa Strauch, Juan Carlos Enrique
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    Rapamycin and WYE-354 suppress human gallbladder cancer xenografts in mice
    (2015) Weber, Helga; Leal, Pamela; Stein, Stefan; Kunkel, Hana; García Cañete, Patricia; Bizama, Carolina; Espinoza, Jaime A.; Riquelme, Ismael; Nervi Nattero, Bruno; Araya, Juan C.; Grez, Manuel; Roa Strauch, Juan Carlos Enrique
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    Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer
    (2017) Weber, Helga; Valbuena Mora, José Rafael; Barbhuiya, Mustafa A.; Stein, Stefan; Kunkel, Hana; García Muñoz, Patricia; Bizama, Carolina; Riquelme, Ismael; Espinoza, Jaime A.; Kurtz, Stephen E.; Tyner, Jeffrey W.; Calderon, Juan Francisco; Corvalán R., Alejandro; Grez, Manuel; Pandey, Akhilesh; Leal Rojas, Pamela; Roa Strauch, Juan Carlos Enrique
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    The Gene Expression Status of the PI3K/AKT/mTOR Pathway in Gastric Cancer Tissues and Cell Lines
    (2016) Riquelme, Ismael; Tapia, Óscar; Espinoza, Jaime A.; Leal, Pamela; Buchegger, Kurt; Sandoval, Alejandra; Bizama, Carolina; Araya, Juan Carlos; Peek, Richard M.; Roa Strauch, Juan Carlos Enrique
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    The inflammatory inception of gallbladder cancer
    (2016) Espinoza, Jaime A.; Bizama, Carolina; García Cañete, Patricia; Ferreccio Readi, Catterina; Javle, Milind; Miquel P., Juan Francisco; Koshiol, Jill; Roa Strauch, Juan Carlos Enrique