Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome

Abstract

TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1α, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading to enhanced vesicular trafficking and secretion. The mut-p53/HIF1α/miR-30d axis potentiates the release of soluble factors and the deposition and remodeling of the ECM, affecting mechano-signaling and stromal cells activation within the tumor microenvironment, thereby enhancing tumor growth and metastatic colonization.

Cancer Stemness: p53 at the Wheel

“…showed that mutant p53 can interact with HIF1α to induce miR-30d expression which promotes tubulo-vesiculation of Golgi apparatus leading to enhanced vesicular trafficking and secretion ( Figure 3A ) ( 127 ). This potentiates the deposition and remodeling of extra-cellular matrix enhancing metastatic colonization and tumorigenesis ( 127 ).…”

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

“…Paracrine oncogenic properties of stromal mut-p53 may be important for patients of the Li Fraumeni familial cancer predisposition syndrome, who develop tumors embedded in a mut-p53 expressing stroma ( 24 , 25 ). Notably, Li-Fraumeni fibroblasts expressing mut-p53 R248Q have an increased rate of global secretion as compared to wild-type p53 expressing cells ( 26 ), suggesting that TP53 mutation may induce this pro-tumorigenic phenotype also in pre-neoplastic tissues. In addition, it has been reported that exposure to environmental cues including hypoxia ( 27 ) and growth factors ( 28 ), as well as inactivation of the Hippo tumor suppressor pathway ( 29 ) may turn wild-type-p53 into a mutant-like structural and functional state ( Figure 2 ), suggesting that mutant-like p53 activities in non-transformed cells of the TME may have wider prevalence and stronger impact than initially appreciated.…”

“…This activity associates with increased NSCLC tumor growth in mouse models, and with adverse prognosis of lung cancer patients ( 38 ). Accordingly, work by our group demonstrated that in breast cancer cells mut-p53 R280K /HIF1α promote ECM deposition and stiffening, thereby sustaining mechano-stimulation and functional activation of CAFs both at primary and secondary tumor sites ( 26 ). Importantly, mut-p53 acts as mechanosensitive oncoprotein, being stabilized and activated downstream to actomyosin dynamics induced by ECM rigidity ( 39 ).…”

“…In this context we recently added further evidence of the synergism between mut-p53 and HIF1α showing that, through cooperative activation of the MIR30D chromatin regulatory region, these oncogenes boost the expression of the onco-miRNA-30d in both hypoxic and normoxic cells ( 26 ). miR-30d was previously reported to promote cancer cell migration/invasion and metastasis by modulating several targets, and indeed it is aberrantly expressed in various tumor contexts ( 45 – 48 ).…”

“…It is tempting to speculate that, through secretion of miR-30d, tumor cells bearing TP53 mutations may contribute to ablating wild-type p53 function in the TME by a non-cell autonomous mechanism. Notably, in cancer cells miR-30d appears to have a negligible effect on the expression of mut-p53 ( 26 ), likely due to the high stability exhibited by mutant p53 oncoproteins in tumor contexts ( 52 ).…”