Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome.

Animals Biopsy Breast Neoplasms / genetics Cell Line, Tumor Cell Transformation, Neoplastic / genetics Female Fibroblasts Gene Expression Regulation, Neoplastic Golgi Apparatus / metabolism Humans Hypoxia-Inducible Factor 1, alpha Subunit / genetics Li-Fraumeni Syndrome / genetics Mice MicroRNAs / metabolism Microtubules / metabolism Mutation Primary Cell Culture Secretory Vesicles / metabolism Signal Transduction / genetics Skin / cytology Tumor Microenvironment / genetics Tumor Suppressor Protein p53 / genetics Xenograft Model Antitumor Assays

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
07 08 2020

Historique:

received: 15 12 2019

accepted: 03 07 2020

entrez: 10 8 2020

pubmed: 10 8 2020

medline: 22 9 2020

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-020-17596-5 PMID: 32770028 PMC: PMC7414119

pubmed: 32770028

doi: 10.1038/s41467-020-17596-5

pii: 10.1038/s41467-020-17596-5

pmc: PMC7414119

doi:

Substances chimiques

HIF1A protein, human 0

Hypoxia-Inducible Factor 1, alpha Subunit 0

MIRN30b microRNA, human 0

MicroRNAs 0

TP53 protein, human 0

Tumor Suppressor Protein p53 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Video-Audio Media

Langues

eng

Sous-ensembles de citation

Pagination

3945

Subventions

Organisme : CIHR

Pays : Canada

Commentaires et corrections

Type : CommentIn

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