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Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT)

Telomere maintenance is necessary to maintain cancer cell unlimited viability. However, the mechanisms maintaining telomere length in colorectal cancer (CRC) have not been extensively investigated. Telomere maintenance mechanisms (TMM) include the re-expression of telomerase or alternative lengtheni...

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Autores principales: Falcinelli, Marta, Dell’Omo, Giulia, Grassi, Elena, Mariella, Elisa, Leto, Simonetta Maria, Scardellato, Sharon, Lorenzato, Annalisa, Arena, Sabrina, Bertotti, Andrea, Trusolino, Livio, Bardelli, Alberto, d’Adda di Fagagna, Fabrizio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9911751/
https://www.ncbi.nlm.nih.gov/pubmed/36759506
http://dx.doi.org/10.1038/s41419-023-05640-3
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author Falcinelli, Marta
Dell’Omo, Giulia
Grassi, Elena
Mariella, Elisa
Leto, Simonetta Maria
Scardellato, Sharon
Lorenzato, Annalisa
Arena, Sabrina
Bertotti, Andrea
Trusolino, Livio
Bardelli, Alberto
d’Adda di Fagagna, Fabrizio
author_facet Falcinelli, Marta
Dell’Omo, Giulia
Grassi, Elena
Mariella, Elisa
Leto, Simonetta Maria
Scardellato, Sharon
Lorenzato, Annalisa
Arena, Sabrina
Bertotti, Andrea
Trusolino, Livio
Bardelli, Alberto
d’Adda di Fagagna, Fabrizio
author_sort Falcinelli, Marta
collection PubMed
description Telomere maintenance is necessary to maintain cancer cell unlimited viability. However, the mechanisms maintaining telomere length in colorectal cancer (CRC) have not been extensively investigated. Telomere maintenance mechanisms (TMM) include the re-expression of telomerase or alternative lengthening of telomeres (ALT). ALT is genetically associated with somatic alterations in alpha-thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) genes. Cells displaying ALT present distinctive features including C-circles made of telomeric DNA, long and heterogenous telomeric tracts, and telomeric DNA co-localized with promyelocytic leukemia (PML) bodies forming so-called ALT-associated PML bodies (APBs). Here, we identified mutations in ATRX and/or DAXX genes in an extensive collection of CRC samples including 119 patient-derived organoids (PDOs) and 232 established CRC cell lines. C-circles measured in CRC PDOs and cell lines showed low levels overall. We also observed that CRC PDOs and cell lines did not display a significant accumulation of APBs or long telomeres with no appreciable differences between wild-type and mutated ATRX/DAXX samples. Overall, our extensive analyses indicate that CRC is not prone to engage ALT, even when carrying genetic lesions in ATRX and/or DAXX, and support the notion that ATRX/DAXX genomic footprints are not reliable predictors of ALT.
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spelling pubmed-99117512023-02-11 Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT) Falcinelli, Marta Dell’Omo, Giulia Grassi, Elena Mariella, Elisa Leto, Simonetta Maria Scardellato, Sharon Lorenzato, Annalisa Arena, Sabrina Bertotti, Andrea Trusolino, Livio Bardelli, Alberto d’Adda di Fagagna, Fabrizio Cell Death Dis Article Telomere maintenance is necessary to maintain cancer cell unlimited viability. However, the mechanisms maintaining telomere length in colorectal cancer (CRC) have not been extensively investigated. Telomere maintenance mechanisms (TMM) include the re-expression of telomerase or alternative lengthening of telomeres (ALT). ALT is genetically associated with somatic alterations in alpha-thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) genes. Cells displaying ALT present distinctive features including C-circles made of telomeric DNA, long and heterogenous telomeric tracts, and telomeric DNA co-localized with promyelocytic leukemia (PML) bodies forming so-called ALT-associated PML bodies (APBs). Here, we identified mutations in ATRX and/or DAXX genes in an extensive collection of CRC samples including 119 patient-derived organoids (PDOs) and 232 established CRC cell lines. C-circles measured in CRC PDOs and cell lines showed low levels overall. We also observed that CRC PDOs and cell lines did not display a significant accumulation of APBs or long telomeres with no appreciable differences between wild-type and mutated ATRX/DAXX samples. Overall, our extensive analyses indicate that CRC is not prone to engage ALT, even when carrying genetic lesions in ATRX and/or DAXX, and support the notion that ATRX/DAXX genomic footprints are not reliable predictors of ALT. Nature Publishing Group UK 2023-02-09 /pmc/articles/PMC9911751/ /pubmed/36759506 http://dx.doi.org/10.1038/s41419-023-05640-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Falcinelli, Marta
Dell’Omo, Giulia
Grassi, Elena
Mariella, Elisa
Leto, Simonetta Maria
Scardellato, Sharon
Lorenzato, Annalisa
Arena, Sabrina
Bertotti, Andrea
Trusolino, Livio
Bardelli, Alberto
d’Adda di Fagagna, Fabrizio
Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT)
title Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT)
title_full Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT)
title_fullStr Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT)
title_full_unstemmed Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT)
title_short Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT)
title_sort colorectal cancer patient-derived organoids and cell lines harboring atrx and/or daxx mutations lack alternative lengthening of telomeres (alt)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9911751/
https://www.ncbi.nlm.nih.gov/pubmed/36759506
http://dx.doi.org/10.1038/s41419-023-05640-3
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