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.

Liver osteopontin is required to prevent the progression of age‐related nonalcoholic fatty liver disease

“…p53 represses some of the SASP in certain conditions and cell types (Wiley et al., 2018). However, p53 also plays a critical enhancing role in SASP production, as many of these SASP factors are directly stimulated by p53, among them the secretion of several cytokines (Pavlakis & Stiewe, 2020). SASP profile can greatly variate depending on the cell type and effector.…”

The Endosomal Recycling Pathway—At the Crossroads of the Cell

“…These have roles in cell–cell communication and ECM remodelling. More and more studies are reporting the involvement of mutant p53 in modulating the cancer ‘secretome’ to promote cancer invasion and metastasis [ 92 ]. RCP has been implicated in the exosome-mediated communication of mutant p53 gain-of-functions between tumour cells and fibroblasts in the stroma and to prime pre-metastatic niches in distant organs [ 93 ].…”

The Mutant p53-Driven Secretome Has Oncogenic Functions in Pancreatic Ductal Adenocarcinoma Cells

“…Many recent studies reveal the role of p53 mutant proteins in the modification of the tumor microenvironment and secretome of cancer cells, altering the secretion of inflammatory cytokines, affecting the crosstalk between cancer and stromal cells, and increasing the extracellular acidification [ 16 , 17 , 18 ]. Cancer aggressiveness is strongly dependent on the composition of the extracellular microenvironment, which is itself affected by the release of proteins by the cancer cells.…”