Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome: Nature Communications

V. Capaci, L. Bascetta, M. Fantuz, G.V. Beznoussenko, R. Sommaggio, V. Cancila, A. Bisso, E. Campaner, A.A. Mironov, J.R. Wiśniewski, L. Ulloa Severino, D. Scaini, F. Bossi, J. Lees, N. Alon, L. Brunga, D. Malkin, S. Piazza, L. Collavin, A. RosatoS. Bicciato, C. Tripodo, F. Mantovani, G. 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. © 2020, The Author(s).
Original languageEnglish
JournalNat. Commun.
Volume11
Issue number1
DOIs
Publication statusPublished - 2020

Keywords

  • histone deacetylase 6
  • microRNA
  • protein p53
  • small interfering RNA
  • transcriptome
  • vasculotropin
  • HIF1A protein, human
  • hypoxia inducible factor 1alpha
  • MIRN30 microRNA, human
  • TP53 protein, human
  • anoxic conditions
  • cancer
  • cell
  • gene expression
  • induced response
  • mutation
  • protein
  • secretion
  • angiogenesis
  • Article
  • atomic force microscopy
  • autopsy
  • autoradiography
  • bioinformatics
  • bioluminescence
  • breast cancer
  • cancer growth
  • cell migration
  • cell proliferation
  • clinical outcome
  • controlled study
  • down regulation
  • endoplasmic reticulum stress
  • female
  • fibroblast
  • gene silencing
  • genetic transfection
  • glycosylation
  • Golgi complex
  • human
  • human cell
  • human tissue
  • immunoblotting
  • immunofluorescence
  • immunohistochemistry
  • immunoprecipitation
  • luciferase assay
  • MDA-MB-231 cell line
  • mechanotransduction
  • microarray analysis
  • mouse
  • nonhuman
  • Notch signaling
  • protein expression
  • protein synthesis
  • real time polymerase chain reaction
  • RNA extraction
  • RNA sequence
  • secretomics
  • site directed mutagenesis
  • skin biopsy
  • tumor growth
  • tumor microenvironment
  • tumor volume
  • tumor xenograft
  • unfolded protein response
  • upregulation
  • wound healing assay
  • animal
  • biopsy
  • breast tumor
  • cell transformation
  • cytology
  • drug screening
  • gene expression regulation
  • genetics
  • Li-Fraumeni syndrome
  • metabolism
  • microtubule
  • pathology
  • primary cell culture
  • secretory vesicle
  • signal transduction
  • skin
  • tumor cell line
  • Animals
  • Biopsy
  • Breast Neoplasms
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Female
  • Fibroblasts
  • Gene Expression Regulation, Neoplastic
  • Golgi Apparatus
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Li-Fraumeni Syndrome
  • Mice
  • MicroRNAs
  • Microtubules
  • Mutation
  • Primary Cell Culture
  • Secretory Vesicles
  • Signal Transduction
  • Skin
  • Tumor Microenvironment
  • Tumor Suppressor Protein p53
  • Xenograft Model Antitumor Assays

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