p53's Extended Reach: The Mutant p53 Secretome

Abstract

p53 suppresses tumorigenesis by activating a plethora of effector pathways. While most of these operate primarily inside of cells to limit proliferation and survival of incipient cancer cells, many extend to the extracellular space. In particular, p53 controls expression and secretion of numerous extracellular factors that are either soluble or contained within extracellular vesicles such as exosomes. As part of the cellular secretome, they execute key roles in cell-cell communication and extracellular matrix remodeling. Mutations in the p53-encoding TP53 gene are the most frequent genetic alterations in cancer cells, and therefore, have profound impact on the composition of the tumor cell secretome. In this review, we discuss how the loss or dominant-negative inhibition of wild-type p53 in concert with a gain of neomorphic properties observed for many mutant p53 proteins, shapes a tumor cell secretome that creates a supportive microenvironment at the primary tumor site and primes niches in distant organs for future metastatic colonization.

Keywords: exosomes; extracellular vesicles; metastasis; p53; pre-metastatic niches; secretome; tumor microenvironment; tumor suppressor.

Figure 1

TP53 mutations shift the cellular secretome from a tumor suppressive secretome driven by wild-type p53 (WTp53) to a cancer-promoting secretome through: loss of WTp53 function (LOF), dominant-negative (DN) inhibition of WTp53 by mutant p53 (mutp53), and gain of neomorphic functions with oncogenic properties (GOF). ECM, extracellular matrix.

Figure 2

Abrogation of the wild-type p53 secretome by TP53 mutations. The senescence-associated secretory phenotype (SASP) driven by wild-type p53 induces senescence in neighboring tumor cells, inhibits angiogenesis, polarizes macrophages to the anti-tumor M1 phenotype, and activates NK and T cells to trigger immune clearance.

Figure 3

Abrogation of the wild-type p53 secretome by TP53 mutations. (A) Wild-type p53 crosstalks to NF-κB in a mostly inhibitory, but sometimes, also cooperative manner. The outcome is context-dependent manner and modulated by, for example, IKKα and the common TP53 codon 72 polymorphism. (B) p53 crosstalk with NF-κB controls apoptosis and impacts on the inflammatory secretome, thereby regulating macrophage polarization, neutrophil recruitment, and angiogenesis. TAM, tumor-associated macrophages.

Figure 4

Mutant p53 shapes the tumor cell secretome at the transcriptional level. Mutant p53 interacts with transcription factors and/or chromatin-modifying enzymes (SWI/SNF and COMPASS) to promote angiogenesis, trigger epithelial-mesenchymal transition (EMT), remodel the extracellular matrix (ECM), and modulate the composition and function of the cellular stroma infiltrate.

Figure 5

Mutant p53 shapes the tumor cell secretome at the exosome level. TP53 mutations abrogate wild-type p53-mediated effects on exosome secretion, size, and cargo and actively control exosomal secretion of miR-1246 and podocalyxin (PODXL), thereby affecting macrophage M1-M2 polarization and extracellular matrix (ECM) remodeling by cancer-associated fibroblasts (CAF).