Naoyuki Iwahashi

Novel Approaches for Detecting TP53 Mutations and Targeted Therapeutic Strategies: Emerging Insights Into Cytoplasmic p53 Aggregates in Ovarian Cancer

ABSTRACT Background Ovarian cancers have been the most lethal gynecologic malignancies worldwide, with survival outcomes remaining poor despite therapeutic advances. Since TP53 is the most frequently mutated gene in ovarian cancers, it highlights the central role of p53 dysfunction in promoting tumor initiation, genomic instability, and progression. Beyond classical loss of transcriptional activity, mutant p53 may exert dominant‐negative effects on residual wild‐type protein and acquire oncogenic gain‐of‐function properties that promote invasion, metastasis, and resistance to chemotherapy. Nevertheless, despite extensive efforts, effective therapeutic agents targeting TP53 ‐mutant tumors remain elusive, representing a major unmet medical need. Methods The published articles were reviewed. Results To detect the TP53 mutations, driven by recent technological innovations, circulating tumor DNA has emerged as a powerful and minimally invasive biomarker that enables the detection of gene mutations and the real‐time monitoring of tumor evolution, minimal residual disease, and therapeutic resistance. Bridging diagnostics and therapy, recent discoveries highlight that cytoplasmic p53 aggregates as a clinically adverse phenotype in high‐grade serous ovarian cancers, elucidating mechanisms of aggregate formation and propagation. By restoring p53 conformation and transcriptional activity through distinct molecular mechanisms, pharmacologic reactivation of mutant p53 holds promise as a novel therapeutic strategy. Conclusion These advances indicate that TP53 disruption, once deemed untargetable, may become a new cornerstone of precision oncology in ovarian cancer.

Sulfated glycosaminoglycans mediate prion-like behavior of p53 aggregates

Significance Approximately 50 human diseases are associated with deposition of abnormally aggregated proteins that propagate in a prion-like manner. The tumor suppressor p53 forms amyloid-like aggregates; however, how p53 aggregates propagate remains unclear. Here, we identified heparan sulfate (HS), the common and major nonprotein component of in vivo deposits of various protein aggregates, as a mediator of prion-like propagation of p53 aggregates in cultured cells. Our immunohistochemical analysis showing codeposition of p53 and highly sulfated domains of HS in ovarian cancer tissues strongly support the role of HS-mediated propagation of p53 aggregates in cancer pathology. Accordingly, our results provide a mechanism of propagation of p53 aggregates that is mediated by HS. Elucidation of detailed biological relevance in cancer is warranted.