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

• Published in: Cell death & disease 2023-02, Vol.14 (2), p.96-96, Article 96
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 14; 14/19; 631/337/103/560; 631/80/103/560; alpha-Thalassemia; Antibodies; Biochemistry; Biomedical and Life Sciences; Cancer; Cell Biology; Cell Culture; Cell Line; Co-Repressor Proteins - genetics; Co-Repressor Proteins - metabolism; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Daxx protein; Humans; Immunology; Intellectual disabilities; Intellectual Disability; Life Sciences; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Mutation; Mutation - genetics; Organoids; Organoids - metabolism; Promyeloid leukemia; Telomerase; Telomerase - genetics; Telomerase - metabolism; Telomere - genetics; Telomere - metabolism; Telomere Homeostasis - genetics; Telomeres; Thalassemia; Tumor cell lines; X-linked Nuclear Protein - genetics; X-linked Nuclear Protein - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-05640-3

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.