Cologne Seminars on Ageing "Evolution of Cells Progressing Through Replicative Crisis to Immortality"

About Dr. Schmidt's talk:
Shortening of telomeres, the repetitive, protective ends of eukaryotic linear chromosomes, restrict the proliferation capacity of human somatic cells by inducing two distinct proliferation barriers: replicative senescence and crisis. During malignant transformation, premalignant cells have to overcome these last barriers and acquire a telomere maintenance mechanism (TMM) to achieve replicative immortality. Currently, replicative crisis, TMM acquisition and the early stages of carcinogenesis are poorly understood. Here, we model and analyze the early stages of tumorigenesis using an in vitro crisis escape model. Out of 81 million IMR90 E6E7 lung fibroblast crisis cells two distinct populations of post-crisis clones emerged: four mortal clones that succumb after proliferating initially, and four immortal clones that maintain their telomeres by telomerase. Single-cell DNA strand-sequencing of crisis cells revealed high genome instability characterized by complex structural variants (SVs). Unexpectedly, the emerging post-crisis clones showed relative few and simple SVs, suggesting that crisis has evolved to stringently counterselect against cells with high genomic instability. However, with accumulating divisions post crisis escape, the genomes of the immortal post-crisis clones evolve and amass additional genomic alterations, including tetraploidization events with subsequent losses and gains of individual chromosomes. Thus, our data indicate that the highly rearranged genomes found in some cancers are not originating from crisis but are rather acquired after crisis escape and immortalization.

This event is aimed at a specialist audience.