Genomic instability in mutant p53 cancer cells upon entotic engulfment
journal contributionposted on 2020-08-27, 15:39 authored by Hannah L Mackay, David Moore, Callum Hall, Nicolai J Birkbak, Mariam Jamal-Hanjani, Saadia A Karim, Vinaya M Phatak, Lucia Piñon, Jennifer P Morton, Charles Swanton, John Le Quesne, Patricia AJ Muller
Cell-in-cell (CIC) structures are commonly seen in tumours. Their biological significance remains unclear, although they have been associated with more aggressive tumours. Here we report that mutant p53 promotes CIC via live cell engulfment. Engulfed cells physically interfere in cell divisions of host cells and for cells without p53 this leads to host cell death. In contrast, mutant p53 host cells survive, display aberrant divisions, multinucleation and tripolar mitoses. In xenograft studies, CIC-rich p53 mutant/null co-cultures show enhanced tumour growth. Furthermore, our results show that CIC is common within lung adenocarcinomas, is an independent predictor of poor outcome and disease recurrence, is associated with mutant p53 expression and correlated to measures of heterogeneity and genomic instability. These findings suggest that pro-tumorigenic entotic engulfment activity is associated with mutant p53 expression, and the two combined are a key factor in genomic instability.
Adenocarcinoma of LungAnimalsCarcinogenesisCell DeathCell Line, TumorCell ProliferationCell-in-Cell FormationDNA DamageDisease Models, AnimalGenomic InstabilityHeterograftsHumansLung NeoplasmsMaleMiceMice, Inbred BALB CMice, TransgenicMitosisMutationNeoplasm Recurrence, LocalPromoter Regions, GeneticTumor Suppressor Protein p53Swanton FC001169