TP53 mutation at codon 179 metabolically reprograms cancer cells to promote invasion

Mutations in the tumor suppressor, TP53 , are prevalent in human cancers; yet their functional implications remain unclear. Through comprehensive pan-cancer database analysis, we identified H179 mutations in TP53 as significantly associated with poor disease-free survival across multiple cancer types. Functional studies in lung, ovarian, and prostate cancer cells overexpressing the p53 ^H179R/Y mutants revealed that these mutants are not only defective in tumor-suppressive functions but also actively promote tumor progression. These mutants induce metabolic reprogramming by increasing neutral lipid levels, lipid droplet formation, and the expression of apolipoprotein E (APOE), leading to enhanced invasiveness in 3D collagen models compared to p53 null cells. Moreover, APOE levels were also elevated in patients whose tumor had mutations at codon 179 of TP53 . These findings underscore the critical role of TP53 codon 179 mutations in driving cancer progression and highlight potential therapeutic targets for mitigating their impact.