Extracellular Vesicles: Messengers of p53 in Tumor-Stroma Communication and Cancer Metastasis

Abstract

Tumor progression to a metastatic and ultimately lethal stage relies on a tumor-supporting microenvironment that is generated by reciprocal communication between tumor and stromal host cells. The tumor-stroma crosstalk is instructed by the genetic alterations of the tumor cells-the most frequent being mutations in the gene Tumor protein p53 (TP53) that are clinically correlated with metastasis, drug resistance and poor patient survival. The crucial mediators of tumor-stroma communication are tumor-derived extracellular vesicles (EVs), in particular exosomes, which operate both locally within the primary tumor and in distant organs, at pre-metastatic niches as the future sites of metastasis. Here, we review how wild-type and mutant p53 proteins control the secretion, size, and especially the RNA and protein cargo of tumor-derived EVs. We highlight how EVs extend the cell-autonomous tumor suppressive activity of wild-type p53 into the tumor microenvironment (TME), and how mutant p53 proteins switch EVs into oncogenic messengers that reprogram tumor-host communication within the entire organism so as to promote metastatic tumor cell dissemination.

Keywords: exosomes; extracellular vesicles; metastatic niche priming; mutant p53; p53; pre-metastatic niche; tumor microenvironment.

Figure 1

Extracellular vesicle biogenesis. Microvesicles are generated by direct outward budding from the plasma membrane. Exosomes are derived from intraluminal vesicles (ILV) generated by inward budding of the limiting membrane of early endosomes and multivesicular bodies (MVB). Endosomal sorting complexes required for transport (ESCRT0-III) and RNA-binding proteins are involved in sorting cargo into ILVs.

Figure 2

p53 status shapes tumor–host communication via extracellular vesicles. On one side (left), wild-type p53 induces the secretion of EVs that relay tumor suppressive signals to the microenvironment. On the other side (right), cancer-associated alterations in p53 status drive tumor progression by neutralizing the secretory effects of wild-type p53 (LOF, loss-of-function; DNE, dominant-negative effect) and/or by creating a mutant p53-specific EV secretome (GOF, gain-of-function) that is likely different for distinct missense mutations.

Figure 3

Wild-type p53 regulates the EVs’ biogenesis, cargo and cancer functions at multiple levels to communicate tumor-suppressive signals to the microenvironment. Stress-induced p53 transactivates TSAP6 and the ESCRT-III subunit CHMP4C, resulting in increased exosome secretion [79,80]. p53 alters exosome size and cargo via ESCRT-0 subunit HGS [81]. DNA damage-triggered p53 acetylation by BAG6/CBP/p300 induces anti-metastatic EV cargo, causing the recruitment of tumor-suppressive patrolling monocytes to sites of future metastasis [82]. p53 suppresses cancer-associated fibroblasts’ (CAF) proliferation by repressing exosomal TP53-targeting miRNAs [83]. p53 supports tumor cell phagocytosis under chemoimmunotherapy by repressing the release of PD-L1-positive EVs [84].

Figure 4

p53 mutants (mutp53) employ EVs to communicate signals to the host microenvironment that promote tumor growth and metastasis. p53 mutants induce the secretion of EVs enriched in selected miRNAs; miR-1246-enriched EVs, due to hnRNPa2b1 SUMOylation, reprogram macrophages to a tumor-supporting M2-like phenotype [67], while the mutp53-induced secretion of miR-21-3p/miR-769-3p EVs activates cancer-associated fibroblasts (CAFs) to secrete cytokines and enhance tumor cell motility via an epithelial-to-mesenchymal transition (EMT) [106]. Via p63 and Rab35, p53 mutants fine-tune exosomal PODXL levels, thereby increasing RCP/DGKα-dependent, pro-invasive integrin recycling in recipient tumor cells and fibroblasts, which leads to enhanced invasion and creates pro-invasive extracellular matrix (ECM) alterations in distant organs resembling pre-metastatic niches [107]. p53 DNA contact mutants, via RCP, increase exosomal HSP90α secretion, leading to pro-metastatic extracellular matrix remodeling via MMP2 [108].