The Complex Interplay Between p53 and Aneuploidy in Cancer

In this thesis, we dived into the complex relationship between p53 and aneuploidy. p53 acts as a central tumor suppressor that responds to diverse cellular stresses, including DNA damage, replication stress, and proteotoxic burden, whereas aneuploidy refers to the state characterized by copy number imbalances that can trigger such stresses. Because p53 activation can limit the proliferation of aneuploid cells, and loss of p53 strongly associates with the presence of aneuploid cells in tumors, p53 has been widely considered a critical safeguard against aneuploidy. However, the extent to which p53 constrains aneuploidy remains unresolved. In this thesis, we challenge the notion of p53 as a universal safeguard against aneuploidy. First, by reviewing previous research we found that the role of p53 in aneuploidy remains unresolved in part due to the use of different experimental models and approaches. Second, large-scale cancer genome dataset analyses showed that, despite a pan-cancer correlation between p53 loss and high degree of aneuploidy, a high degree of aneuploidy can occur across cancer types irrespective of p53 status, indicating that p53 loss is neither sufficient nor necessary for widespread aneuploidy. In addition, we found that loss of p53 correlates with the degree of aneuploidy only in a subset of cancer types, and is more universally related to copy number losses. Third, we showed experimentally that p53-proficient non-transformed cells tolerate a low degree of aneuploidy and in one unique case even underwent a whole-genome doubling (WGD) event. Accumulation of more complex aneuploid cells after WGD occurred only upon p53 loss, suggesting that it increases tolerance to aneuploidy rather than being absolutely required. Finally, real-time characterization of p53 dynamics following chromosome mis-segregation uncovered a delayed p53 activation and showed that, as predicted, aneuploid cells could continue to proliferate without activating p53. Collectively, these findings underscore that the role of p53 in aneuploidy surveillance is highly context-specific rather than universal, and highlight a key outstanding question: what explains whether cells mount a p53 response following aneuploidy? Addressing this requires disentangling the mechanisms of p53 response and the diverse intrinsic features of the states we define as aneuploidy. This work aids in this endeavor by refining our understanding of the aneuploidy–p53 axis and provides a conceptual framework for future investigations into how cells tolerate or limit aneuploidy in cancer.