Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome

Valeria Capaci, Lorenzo Bascetta, Marco Fantuz, Galina V. Beznoussenko, Roberta Sommaggio, Valeria Cancila, Andrea Bisso, Elena Campaner, Alexander A. Mironov, Jacek R. Wiśniewski, Luisa Ulloa Severino, Denis Scaini, Fleur Bossi, Jodi Lees, Noa Alon, Ledia Brunga, David Malkin, Silvano Piazza, Licio Collavin, Antonio RosatoSilvio Bicciato, Claudio Tripodo, Fiamma Mantovani, Giannino Del Sal

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number3945
Pages (from-to)1-19
Number of pages19
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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