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Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN

BACKGROUND: Colorectal cancer (CRC) represents the fourth leading cause of cancer-related deaths. The heterogeneity of CRC identity limits the usage of cell lines to study this type of tumor because of the limited representation of multiple features of the original malignancy. Patient-derived colon...

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Autores principales: Codrich, Marta, Dalla, Emiliano, Mio, Catia, Antoniali, Giulia, Malfatti, Matilde Clarissa, Marzinotto, Stefania, Pierobon, Mariaelena, Baldelli, Elisa, Di Loreto, Carla, Damante, Giuseppe, Terrosu, Giovanni, Pucillo, Carlo Ennio Michele, Tell, Gianluca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215814/
https://www.ncbi.nlm.nih.gov/pubmed/34154611
http://dx.doi.org/10.1186/s13046-021-01986-8
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author Codrich, Marta
Dalla, Emiliano
Mio, Catia
Antoniali, Giulia
Malfatti, Matilde Clarissa
Marzinotto, Stefania
Pierobon, Mariaelena
Baldelli, Elisa
Di Loreto, Carla
Damante, Giuseppe
Terrosu, Giovanni
Pucillo, Carlo Ennio Michele
Tell, Gianluca
author_facet Codrich, Marta
Dalla, Emiliano
Mio, Catia
Antoniali, Giulia
Malfatti, Matilde Clarissa
Marzinotto, Stefania
Pierobon, Mariaelena
Baldelli, Elisa
Di Loreto, Carla
Damante, Giuseppe
Terrosu, Giovanni
Pucillo, Carlo Ennio Michele
Tell, Gianluca
author_sort Codrich, Marta
collection PubMed
description BACKGROUND: Colorectal cancer (CRC) represents the fourth leading cause of cancer-related deaths. The heterogeneity of CRC identity limits the usage of cell lines to study this type of tumor because of the limited representation of multiple features of the original malignancy. Patient-derived colon organoids (PDCOs) are a promising 3D-cell model to study tumor identity for personalized medicine, although this approach still lacks detailed characterization regarding molecular stability during culturing conditions. Correlation analysis that considers genomic, transcriptomic, and proteomic data, as well as thawing, timing, and culturing conditions, is missing. METHODS: Through integrated multi–omics strategies, we characterized PDCOs under different growing and timing conditions, to define their ability to recapitulate the original tumor. RESULTS: Whole Exome Sequencing allowed detecting temporal acquisition of somatic variants, in a patient-specific manner, having deleterious effects on driver genes CRC-associated. Moreover, the targeted NGS approach confirmed that organoids faithfully recapitulated patients’ tumor tissue. Using RNA-seq experiments, we identified 5125 differentially expressed transcripts in tumor versus normal organoids at different time points, in which the PTEN pathway resulted of particular interest, as also confirmed by further phospho-proteomics analysis. Interestingly, we identified the PTEN c.806_817dup (NM_000314) mutation, which has never been reported previously and is predicted to be deleterious according to the American College of Medical Genetics and Genomics (ACMG) classification. CONCLUSION: The crosstalk of genomic, transcriptomic and phosphoproteomic data allowed to observe that PDCOs recapitulate, at the molecular level, the tumor of origin, accumulating mutations over time that potentially mimic the evolution of the patient’s tumor, underlining relevant potentialities of this 3D model. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-01986-8.
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spelling pubmed-82158142021-06-23 Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN Codrich, Marta Dalla, Emiliano Mio, Catia Antoniali, Giulia Malfatti, Matilde Clarissa Marzinotto, Stefania Pierobon, Mariaelena Baldelli, Elisa Di Loreto, Carla Damante, Giuseppe Terrosu, Giovanni Pucillo, Carlo Ennio Michele Tell, Gianluca J Exp Clin Cancer Res Research BACKGROUND: Colorectal cancer (CRC) represents the fourth leading cause of cancer-related deaths. The heterogeneity of CRC identity limits the usage of cell lines to study this type of tumor because of the limited representation of multiple features of the original malignancy. Patient-derived colon organoids (PDCOs) are a promising 3D-cell model to study tumor identity for personalized medicine, although this approach still lacks detailed characterization regarding molecular stability during culturing conditions. Correlation analysis that considers genomic, transcriptomic, and proteomic data, as well as thawing, timing, and culturing conditions, is missing. METHODS: Through integrated multi–omics strategies, we characterized PDCOs under different growing and timing conditions, to define their ability to recapitulate the original tumor. RESULTS: Whole Exome Sequencing allowed detecting temporal acquisition of somatic variants, in a patient-specific manner, having deleterious effects on driver genes CRC-associated. Moreover, the targeted NGS approach confirmed that organoids faithfully recapitulated patients’ tumor tissue. Using RNA-seq experiments, we identified 5125 differentially expressed transcripts in tumor versus normal organoids at different time points, in which the PTEN pathway resulted of particular interest, as also confirmed by further phospho-proteomics analysis. Interestingly, we identified the PTEN c.806_817dup (NM_000314) mutation, which has never been reported previously and is predicted to be deleterious according to the American College of Medical Genetics and Genomics (ACMG) classification. CONCLUSION: The crosstalk of genomic, transcriptomic and phosphoproteomic data allowed to observe that PDCOs recapitulate, at the molecular level, the tumor of origin, accumulating mutations over time that potentially mimic the evolution of the patient’s tumor, underlining relevant potentialities of this 3D model. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-01986-8. BioMed Central 2021-06-21 /pmc/articles/PMC8215814/ /pubmed/34154611 http://dx.doi.org/10.1186/s13046-021-01986-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Codrich, Marta
Dalla, Emiliano
Mio, Catia
Antoniali, Giulia
Malfatti, Matilde Clarissa
Marzinotto, Stefania
Pierobon, Mariaelena
Baldelli, Elisa
Di Loreto, Carla
Damante, Giuseppe
Terrosu, Giovanni
Pucillo, Carlo Ennio Michele
Tell, Gianluca
Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN
title Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN
title_full Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN
title_fullStr Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN
title_full_unstemmed Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN
title_short Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN
title_sort integrated multi-omics analyses on patient-derived crc organoids highlight altered molecular pathways in colorectal cancer progression involving pten
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215814/
https://www.ncbi.nlm.nih.gov/pubmed/34154611
http://dx.doi.org/10.1186/s13046-021-01986-8
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