Telomere-centromere-driven genomic instability contributes to karyotype evolution in a mouse model of melanoma.
Aneuploidy and chromosomal instability (CIN) are hallmarks of most solid tumors. These alterations may result from inaccurate chromosomal segregation during mitosis, which can occur through several mechanisms including defective telomere metabolism, centrosome amplification, dysfunctional centromeres, and/or defective spindle checkpoint control. In this work, we used an in vitro murine melanoma model that uses a cellular adhesion blockade as a transforming factor to characterize telomeric and centromeric alterations that accompany melanocyte transformation. To study the timing of the occurrence of telomere shortening in this transformation model, we analyzed the profile of telomere length by quantitative fluorescent in situ hybridization and found that telomere length significantly decreased as additional rounds of cell adhesion blockages were performed. Together with it, an increase in telomere-free ends and complex karyotypic aberrations were also found, which include Robertsonian fusions in 100% of metaphases of the metastatic melanoma cells. These findings are in agreement with the idea that telomere length abnormalities seem to be one of the earliest genetic alterations acquired in the multistep process of malignant transformation and that telomere abnormalities result in telomere aggregation, breakage-bridge-fusion cycles, and CIN. Another remarkable feature of this model is the abundance of centromeric instability manifested as centromere fragments and centromeric fusions. Taken together, our results illustrate for this melanoma model CIN with a structural signature of centromere breakage and telomeric loss.
Silva
Amanda Gonçalves Dos Santos
AG
Department of Microbiology, Immunology, and Parasitology, Universidade Federal de São Paulo-UNIFESP, São Paulo, SP, Brazil.
Graves
Herbert Alexander
HA
Guffei
Amanda
A
Ricca
Tatiana Iervolino
TI
Mortara
Renato Arruda
RA
Jasiulionis
Miriam Galvonas
MG
Mai
Sabine
S
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002503:Centromere / Q000235:genetics*; D002869:Chromosome Aberrations; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D042822:Genomic Instability; D017404:In Situ Hybridization, Fluorescence; D008546:Melanoma, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D032681:Spectral Karyotyping; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics*
D019098:Telomerase