Context is everything: extrinsic signalling and gain-of-function p53 mutants

Abstract

The TP53 genomic locus is a target of mutational events in at least half of cancers. Despite several decades of study, a full consensus on the relevance of the acquisition of p53 gain-of-function missense mutants has not been reached. Depending on cancer type, type of mutations and other unidentified factors, the relevance for tumour development and progression of the oncogenic signalling directed by p53 mutants might significantly vary, leading to inconsistent observations that have fuelled a long and fierce debate in the field. Here, we discuss how interaction with the microenvironment and stressors might dictate the gain-of-function effects exerted by individual mutants. We report evidence from the most recent literature in support of the context dependency of p53 mutant biology. This perspective article aims to raise a discussion in the field on the relevance that context might have on p53 gain-offunction mutants, assessing whether this should generally be considered a cell non-autonomous process. Facts • Mutant p53 GOF effects have been shown to vary in different settings, potentially depending on cancer types, experimental models and conditions. • Reciprocal interaction between microenvironment and mutant p53 GOF effects exists.

Key Players in the Mutant p53 Team: Small Molecules, Gene Editing, Immunotherapy

“…Mutant p53 proteins can form heterotetramers with WT p53, hampering the function of the latter in tumor suppression (21). The primary outcome of TP53 mutations leading to loss of WT p53 functions is the abrogation of its intrinsic tumor suppressive responses such as senescence and apoptosis, while gain-of-function mutant p53 proteins enhance tumor progression, metastatic potential, and drug resistance, greatly contributing to the malignant cellular phenotype (22)(23)(24).…”

Mutant p53 in Cancer Progression and Targeted Therapies

“…Functionally, p53 mutants (mutp53) not only lead to the loss of wild-type p53 functions, but can also result in a dominant negative effect by forming hetero-tetramers with the remaining wild-type p53 expressed from the other wild-type allele. p53 mutations are usually followed by the loss of heterozygosity (LOH) at the remaining wild-type TP53 allele, leading to the complete loss of wild-type p53 in late-stage tumors, and further confer these cancer cells a selective advantage during cancer development (8,9). Most p53 missense mutants acquire oncogenic gain-of-function (GOF) activities.…”

Loss of p53 in mesenchymal stem cells promotes alteration of bone remodeling through negative regulation of osteoprotegerin

“…Indeed, while p53 is a powerful regulator of cell death, a crucial mechanism for its role in cancer development [23][24][25][26], it has a basic effect on metabolism [27,28] and other biologic processes [28,29] including the regulation of MSCs [30,31]. It is evident that cancer cells can selectively silence p53 activities in cancer stromal cells, thereby molding the cancer stroma to facilitate cancer progression [32,33]. Indeed, inactivation of p53 and retinoblastoma gene in bone marrow derived MSCs can promote the development of osteosarcoma-like cancer when transplanted in immunodeficient mice [34].…”