Amplifying Tumor-Stroma Communication: An Emerging Oncogenic Function of Mutant p53

Abstract

TP53 mutations are widespread in human cancers. An expanding body of evidence highlights that, in addition to their manifold cell-intrinsic activities boosting tumor progression, missense p53 mutants enhance the ability of tumor cells to communicate amongst themselves and with the tumor stroma, by affecting both the quality and the quantity of the cancer secretome. In this review, we summarize recent literature demonstrating that mutant p53 enhances the production of growth and angiogenic factors, inflammatory cytokines and chemokines, modulates biochemical and biomechanical properties of the extracellular matrix, reprograms the cell trafficking machinery to enhance secretion and promote recycling of membrane proteins, and affects exosome composition. All these activities contribute to the release of a promalignant secretome with both local and systemic effects, that is key to the ability of mutant p53 to fuel tumor growth and enable metastatic competence. A precise knowledge of the molecular mechanisms underlying the interplay between mutant p53 and the microenvironment is expected to unveil non-invasive biomarkers and actionable targets to blunt tumor aggressiveness.

Keywords: cancer secretome; missense mutant p53; precision therapy; tumor microenvironment; vesicular trafficking.

Figure 1

mut-p53 alters the communication of tumor cells with their microenvironment. In tumor cells mut-p53 interacts with a plethora of transcription factors including NF‐κB, HIFs, and STATs, and regulates the expression of genes encoding secreted proteins. This activity alters the composition of the tumor secretome and hereby the communication of tumor cells among them and with non-transformed stromal cell populations. Mut-p53 driven secretion of soluble proteins, including cytokines/chemokines and growth factors, induces tumor cell invasion and migration, immune evasion, tumor-promoting inflammation and angiogenesis. In addition, mut-p53 interferes with the function of the cytoplasmic DNA sensing machinery, i.e. cGAS-STING-TBK1 complex, abrogating type I interferon response and disabling the innate immune response. Moreover, mut-p53 stimulates secretion of extracellular matrix (ECM) components and matrix remodeling enzymes, thereby altering the biochemical and biomechanical properties of the ECM and promoting activation of Cancer Associated Fibroblasts (CAFs). This also results in cancer cell mechanostimulation, sustaining the stabilization of mut-p53 protein. By inducing the expression of miR-30d (see text for details), mut-p53 fosters diacylglycerol (DAG) signaling in the Golgi Apparatus, causing morphological and functional alterations known as Golgi Tubulo-Vesiculation, thus enhancing total protein secretion. Persistent ER stress, consequent to enhanced secretion, evokes several mut-p53 activities that support cell survival, including modulation of the unfolded protein response (UPR). By sustaining EGFR and integrin signaling via the Rab-coupling protein (RCP) pathway and dynamin-1/APPL1 endosome feedback loop, mut-p53 facilitates cancer cell migration and invasion. Finally, mut-p53 modulates tumor cell messaging also through exosome secretion. The release of podocalyxin-rich (PODXL) exosomes contributes to activate CAFs and promotes ECM remodeling; mut-p53 dependent release of exosomes enriched for miR-1246 induces macrophage polarization towards pro-tumorigenic M2 phenotype, further stoking tumor promoting inflammation.

Figure 2

Crosstalk between mut-p53 and HIF1α within tumor tissues. In tumors, mut-p53 sustains HIF1α function in both normoxic and hypoxic conditions. In normoxic conditions, mut-p53 interacts and inhibits the p63 tumor suppressor, thereby abrogating SHARP1-mediated degradation of HIF1α. In hypoxic conditions, HIF1α is stabilized by loss of VHL- dependent ubiquitination independently of p53 status. In both conditions mut-p53 is able to bind and cooperate with HIF1α at the chromatin level to promote expression of hypoxia responsive genes, ECM components (e.g. type VIIa1 collagen and laminin-γ2), miR-30d, and other tumor-promoting HIF1α target genes. Moreover, p53 and HIF1α are connected by a positive feedback loop. Under hypoxia, and likely in other HIF1α stabilizing conditions, HIF-1α upregulates the TP53 promoter, driving the expression of p53, either wild-type or mutant. Once translated, wild-type p53 may undergo hypoxia-induced conformation changes acquiring a mutant-like (ml) phenotype. Both mut-p53 and ml-p53 bind HIF-1α protecting it from degradation, and chaperone HIF-1α to hypoxia-responsive elements (HREs), finally enhancing HIF1α transcriptional activity.