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 Rosato, Silvio Bicciato, Claudio Tripodo, Fiamma Mantovani and Giannino Del Sal ()
Additional contact information
Valeria Capaci: Laboratorio Nazionale CIB (LNCIB)
Lorenzo Bascetta: Laboratorio Nazionale CIB (LNCIB)
Marco Fantuz: Laboratorio Nazionale CIB (LNCIB)
Galina V. Beznoussenko: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM)
Roberta Sommaggio: Veneto Institute of Oncology IOV-IRCCS
Valeria Cancila: University of Palermo, School of Medicine
Andrea Bisso: Laboratorio Nazionale CIB (LNCIB)
Elena Campaner: Laboratorio Nazionale CIB (LNCIB)
Alexander A. Mironov: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM)
Jacek R. Wiśniewski: Max Planck Institute of Biochemistry
Luisa Ulloa Severino: Università degli Studi di Trieste
Denis Scaini: International School for Advanced Studies (SISSA)
Fleur Bossi: Università degli Studi di Trieste
Jodi Lees: The Hospital for Sick Children
Noa Alon: The Hospital for Sick Children
Ledia Brunga: The Hospital for Sick Children
David Malkin: The Hospital for Sick Children
Silvano Piazza: Laboratorio Nazionale CIB (LNCIB)
Licio Collavin: Laboratorio Nazionale CIB (LNCIB)
Antonio Rosato: Veneto Institute of Oncology IOV-IRCCS
Silvio Bicciato: University of Modena and Reggio Emilia
Claudio Tripodo: University of Palermo, School of Medicine
Fiamma Mantovani: Laboratorio Nazionale CIB (LNCIB)
Giannino Del Sal: Laboratorio Nazionale CIB (LNCIB)

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17596-5

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