Abstract SY07-01: p53-mediated stem cell competition: Insights into mechanisms of clonal dominance

Abstract

Abstract TP53 Mutations confer clonal advantage in several tissues contributing to tumorigenesis. It has traditionally been proposed that heightened resistance to apoptosis/cell cycle arrest can account for clonal advantage. P53 mediated clonal dominance has also been observed in cultured embryonic stem (ES) cells, though it is not clear how this is established. Using live cell imaging we show that human ES cells (hESCs) mutant for TP53 induce death of hES-WT cells and outcompete them. Competition is mediated by apoptosis induction and requires direct cell contact, as in co-cultures of hES-P53KO and hES-WT cells where contact is prevented competition is not observed. To ask if hES-P53KO competition is mediated by mechanical interactions, we cultured cells on deformable membranes to measure their resistance to cell compaction. Interestingly, while hES-WT cells displayed apoptosis induction upon cell compaction, hES-P53KO cells were resistant to compaction-induced apoptosis. We suggest that differential sensitivity to compaction in crowded cultures/tissues can drive p53-induced competitive cell elimination. Identifying the mechanisms by which p53 confers resistance to cell compaction could lead to novel actionable targets to prevent the expansion of p53 mutant stem cells in cancerous and pre-cancerous lesions. Citation Format: Eugenia Piddini. p53-mediated stem cell competition: Insights into mechanisms of clonal dominance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY07-01.