Mutant p53 on the Path to Metastasis

Abstract

Metastasis contributes to the vast majority of cancer-related mortality. Regulatory mechanisms of the multistep invasion-metastasis cascade are being unraveled. TP53 is the most frequently mutated gene across human cancers. Accumulating evidence has shown that mutations of TP53 not only lead to loss of function or dominant negative effects, but also promotes a gain of function. Specifically, gain of function mutant p53 promotes cancer cell motility, invasion, and metastasis. Here, we summarize the mechanisms and functions of mutant p53 that foster metastasis in different types of cancers. We also discuss the prognostic value of mutant p53 and current status of therapeutic strategies targeting mutant p53. Future studies will shed light on discovering novel mechanisms of mutant p53-driven cancer metastasis and developing innovative therapeutics to improve clinical outcomes in patients harboring p53 mutations.

Keywords: epithelial-to-mesenchymal transition (EMT); extracellular matrix (ECM); metastasis; mutant p53; receptor tyrosine kinase (RTK); therapeutics.

Figure 1:. Mechanisms of mutant p53 mediating metastasis.

Mutant p53 promotes cell motility, invasion and metastasis through multiple mechanisms, including regulating epithelial-to-mesenchymal transition (EMT) (labeled in yellow), regulating cell-extracellular matrix(ECM) interactions (labeled in purple), promoting receptor tyrosine kinase (RTK) signaling (labeled in green) and other recently revealed novel mechanisms (labeled in turquoise). Furthermore, interactions of mutant p53 with binding partners serve as an important mechanism to mediate these effects. For example, the binding of mutant p53 with p63, p73, Sp1, or ID4 transcriptionally activates downstream pathways to promote metastasis.

Figure 2:. Therapeutic strategies targeting mutant p53

Strategies targeting mutant p53 include the following: (i) restoring mutant p53 to wild-type p53 structure and function; (ii) destabilizing mutant p53 to deplete the protein; (iii) inhibition of the interactions of mutant p53 with its binding partners to dampen transcriptional regulatory activity; and iv) targeting mutant p53 downstream pathways. Future strategy may involve adoptive T cell therapy against mutant p53 neoepitopes.