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Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome

Author

Listed:
  • Valeria Capaci

    (Laboratorio Nazionale CIB (LNCIB))

  • Lorenzo Bascetta

    (Laboratorio Nazionale CIB (LNCIB)
    International School for Advanced Studies (SISSA))

  • Marco Fantuz

    (Laboratorio Nazionale CIB (LNCIB)
    International School for Advanced Studies (SISSA))

  • 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)
    IEO, European Institute of Oncology IRCCS)

  • Elena Campaner

    (Laboratorio Nazionale CIB (LNCIB)
    Università degli Studi di Trieste)

  • 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
    University of Toronto)

  • Silvano Piazza

    (Laboratorio Nazionale CIB (LNCIB))

  • Licio Collavin

    (Laboratorio Nazionale CIB (LNCIB)
    Università degli Studi di Trieste)

  • Antonio Rosato

    (Veneto Institute of Oncology IOV-IRCCS
    University of Padova)

  • Silvio Bicciato

    (University of Modena and Reggio Emilia)

  • Claudio Tripodo

    (University of Palermo, School of Medicine)

  • Fiamma Mantovani

    (Laboratorio Nazionale CIB (LNCIB)
    Università degli Studi di Trieste)

  • Giannino Del Sal

    (Laboratorio Nazionale CIB (LNCIB)
    Fondazione Istituto FIRC di Oncologia Molecolare (IFOM)
    Università degli Studi di Trieste)

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.

Suggested Citation

  • Valeria Capaci & Lorenzo Bascetta & Marco Fantuz & Galina V. Beznoussenko & Roberta Sommaggio & Valeria Cancila & Andrea Bisso & Elena Campaner & Alexander A. Mironov & Jacek R. Wiśniewski & Luisa Ull, 2020. "Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17596-5
    DOI: 10.1038/s41467-020-17596-5
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    Cited by:

    1. Giovanni Tosi & Alessandro Paoli & Gaia Zuccolotto & Emilia Turco & Manuela Simonato & Daniela Tosoni & Francesco Tucci & Pietro Lugato & Monica Giomo & Nicola Elvassore & Antonio Rosato & Paola Cogo , 2024. "Cancer cell stiffening via CoQ10 and UBIAD1 regulates ECM signaling and ferroptosis in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    2. Ori Hassin & Nishanth Belugali Nataraj & Michal Shreberk-Shaked & Yael Aylon & Rona Yaeger & Giulia Fontemaggi & Saptaparna Mukherjee & Martino Maddalena & Adi Avioz & Ortal Iancu & Giuseppe Mallel & , 2022. "Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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