The Amyloid State of Mutant p53 in Cancer

Mutations in TP53, the most frequently altered gene in human cancer, have long been interpreted within a genetic framework centered on loss of tumor-suppressive function and dominant-negative inhibition. Here, we highlight an emerging paradigm in which mutant p53 operates as a protein conformational disease. A growing body of evidence demonstrates that many cancer-associated p53 mutants adopt an amyloid-like state driven by structural destabilization of the DNA-binding domain, exposing aggregation-prone sequences that nucleate β-sheet-rich oligomers and fibrils. These aggregates exhibit prion-like properties, enabling templated misfolding and self-propagation of aberrant p53 conformations within cells. Beyond intracellular accumulation, recent experimental findings suggest that p53 aggregates may be transferred between cells via extracellular vesicles and heparan sulfate proteoglycan-mediated uptake. However, whether such transfer results in sustained tissue-level propagation within human tumors remains to be established. This proposed "seed-and-spread" model provides an emerging conceptual framework for understanding tumor heterogeneity and disease evolution beyond genetic alterations alone. Clinically, amyloid-like p53 aggregates have been detected in multiple malignancies, including ovarian, breast, and lung cancers, where they are associated with aggressive phenotypes, therapeutic resistance, and poor patient outcomes. These observations indicate that the conformational state of p53 represents a critical but previously underappreciated determinant of tumor behavior. Reframing mutant p53 as a self-propagating oncogenic proteinopathy bridges cancer biology with the principles of neurodegenerative disease and opens new therapeutic opportunities. Targeting the aggregation process, restoring native folding, promoting degradation of misfolded p53, or interrupting intercellular transmission may enable direct intervention against TP53-mutant cancers, which account for nearly half of all human malignancies. This perspective establishes protein misfolding and conformational propagation as central drivers of oncogenesis and highlights a new frontier for precision oncology.