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BSBM-17 NOVEL VALIDATED PATIENT-DERIVED MODELS OF A RECTAL CANCER BRAIN METASTASIS

Colorectal adenocarcinomas (CRC) rarely metastasize to the brain, however, survival rates in patients with colorectal brain metastases (CBM) are short, with a median survival of only 4 months from diagnosis. Currently, no evidence-based treatment options against these rare brain metastases are avail...

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Autores principales: Barros Guinle, Maria Isabel, Tran, Caitlynn To-Dyuen, Nasajpour, Emon, Xing, Yao Lulu, Nakano, Michitaka, Nair, Indu, Sathe, Anuja, Nirschl, Jeffrey, Granucci, Monica, Prolo, Laura M, Ji, Hanlee P, Vogel, Hannes, Lim, Michael, Hayden-Gephart, Melanie, Kuo, Calvin, Petritsch, Claudia K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10402389/
http://dx.doi.org/10.1093/noajnl/vdad070.013
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author Barros Guinle, Maria Isabel
Tran, Caitlynn To-Dyuen
Nasajpour, Emon
Xing, Yao Lulu
Nakano, Michitaka
Nair, Indu
Sathe, Anuja
Nirschl, Jeffrey
Granucci, Monica
Prolo, Laura M
Ji, Hanlee P
Vogel, Hannes
Lim, Michael
Hayden-Gephart, Melanie
Kuo, Calvin
Petritsch, Claudia K
author_facet Barros Guinle, Maria Isabel
Tran, Caitlynn To-Dyuen
Nasajpour, Emon
Xing, Yao Lulu
Nakano, Michitaka
Nair, Indu
Sathe, Anuja
Nirschl, Jeffrey
Granucci, Monica
Prolo, Laura M
Ji, Hanlee P
Vogel, Hannes
Lim, Michael
Hayden-Gephart, Melanie
Kuo, Calvin
Petritsch, Claudia K
author_sort Barros Guinle, Maria Isabel
collection PubMed
description Colorectal adenocarcinomas (CRC) rarely metastasize to the brain, however, survival rates in patients with colorectal brain metastases (CBM) are short, with a median survival of only 4 months from diagnosis. Currently, no evidence-based treatment options against these rare brain metastases are available (PMC). Therefore, characterization of these tumors and development of targeted therapies are imperative. Optimal models for neoplasms heighten the notoriously low success rate of bench-to-bedside translation. Historically, brain cancer metastases models are established cell lines grown on plastic and transplanted as xenografts (Valiente; PMC7572582). Genomic drift, lack of genetic accuracy and heterogeneity, caused by serial passaging on plastic and in high-serum media, are frequent limitations of these models. Growth in defined media without serum and as 3-dimensional (3-D) spheroids or organoids is thought to improve the fidelity of cancer cell lines (Lee; PMID:16697959; Lo; PMC820864). Despite significant efforts of large collaborative projects (https://hcmi-searchable-catalog.nci.nih.gov/), 3-D rectal brain cancer metastasis models have not been reported. To address this unmet medical need, we developed 3-D (suspension, organoid) cultures of a rectal adenocarcinoma brain metastasis with moderate to focally poor differentiation. Next-generation sequencing, expression profiling, and immunohistochemistry were performed to validate our models. Our data confirmed that the PDO model contains tumor cells; pathogenic alterations and expression profiles in the models largely match that of the original tumor. Overall, we detected a significant phenotypic overlap with the original tumor sample. Spatial profiling and PDO-derived xenografts are in progress and will facilitate experimental therapeutics. Taken together, our models retained tumor heterogeneity and fidelity from the primary tumor, making this one of the first studies to establish 3-D patient-derived models for disease progression in rectal cancer brain metastases. Collectively, these models will be valuable translational tools for future exploration of targeted therapy, which remains absent in this disease process.
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spelling pubmed-104023892023-08-05 BSBM-17 NOVEL VALIDATED PATIENT-DERIVED MODELS OF A RECTAL CANCER BRAIN METASTASIS Barros Guinle, Maria Isabel Tran, Caitlynn To-Dyuen Nasajpour, Emon Xing, Yao Lulu Nakano, Michitaka Nair, Indu Sathe, Anuja Nirschl, Jeffrey Granucci, Monica Prolo, Laura M Ji, Hanlee P Vogel, Hannes Lim, Michael Hayden-Gephart, Melanie Kuo, Calvin Petritsch, Claudia K Neurooncol Adv Final Category: Basic Science of Brain Metastases Colorectal adenocarcinomas (CRC) rarely metastasize to the brain, however, survival rates in patients with colorectal brain metastases (CBM) are short, with a median survival of only 4 months from diagnosis. Currently, no evidence-based treatment options against these rare brain metastases are available (PMC). Therefore, characterization of these tumors and development of targeted therapies are imperative. Optimal models for neoplasms heighten the notoriously low success rate of bench-to-bedside translation. Historically, brain cancer metastases models are established cell lines grown on plastic and transplanted as xenografts (Valiente; PMC7572582). Genomic drift, lack of genetic accuracy and heterogeneity, caused by serial passaging on plastic and in high-serum media, are frequent limitations of these models. Growth in defined media without serum and as 3-dimensional (3-D) spheroids or organoids is thought to improve the fidelity of cancer cell lines (Lee; PMID:16697959; Lo; PMC820864). Despite significant efforts of large collaborative projects (https://hcmi-searchable-catalog.nci.nih.gov/), 3-D rectal brain cancer metastasis models have not been reported. To address this unmet medical need, we developed 3-D (suspension, organoid) cultures of a rectal adenocarcinoma brain metastasis with moderate to focally poor differentiation. Next-generation sequencing, expression profiling, and immunohistochemistry were performed to validate our models. Our data confirmed that the PDO model contains tumor cells; pathogenic alterations and expression profiles in the models largely match that of the original tumor. Overall, we detected a significant phenotypic overlap with the original tumor sample. Spatial profiling and PDO-derived xenografts are in progress and will facilitate experimental therapeutics. Taken together, our models retained tumor heterogeneity and fidelity from the primary tumor, making this one of the first studies to establish 3-D patient-derived models for disease progression in rectal cancer brain metastases. Collectively, these models will be valuable translational tools for future exploration of targeted therapy, which remains absent in this disease process. Oxford University Press 2023-08-04 /pmc/articles/PMC10402389/ http://dx.doi.org/10.1093/noajnl/vdad070.013 Text en © The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Final Category: Basic Science of Brain Metastases
Barros Guinle, Maria Isabel
Tran, Caitlynn To-Dyuen
Nasajpour, Emon
Xing, Yao Lulu
Nakano, Michitaka
Nair, Indu
Sathe, Anuja
Nirschl, Jeffrey
Granucci, Monica
Prolo, Laura M
Ji, Hanlee P
Vogel, Hannes
Lim, Michael
Hayden-Gephart, Melanie
Kuo, Calvin
Petritsch, Claudia K
BSBM-17 NOVEL VALIDATED PATIENT-DERIVED MODELS OF A RECTAL CANCER BRAIN METASTASIS
title BSBM-17 NOVEL VALIDATED PATIENT-DERIVED MODELS OF A RECTAL CANCER BRAIN METASTASIS
title_full BSBM-17 NOVEL VALIDATED PATIENT-DERIVED MODELS OF A RECTAL CANCER BRAIN METASTASIS
title_fullStr BSBM-17 NOVEL VALIDATED PATIENT-DERIVED MODELS OF A RECTAL CANCER BRAIN METASTASIS
title_full_unstemmed BSBM-17 NOVEL VALIDATED PATIENT-DERIVED MODELS OF A RECTAL CANCER BRAIN METASTASIS
title_short BSBM-17 NOVEL VALIDATED PATIENT-DERIVED MODELS OF A RECTAL CANCER BRAIN METASTASIS
title_sort bsbm-17 novel validated patient-derived models of a rectal cancer brain metastasis
topic Final Category: Basic Science of Brain Metastases
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10402389/
http://dx.doi.org/10.1093/noajnl/vdad070.013
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