Translational control of breast cancer plasticity.

5' Untranslated Regions / genetics Antineoplastic Agents / pharmacology Breast Neoplasms / drug therapy Cell Hypoxia Cell Line, Tumor Eukaryotic Initiation Factor-2 / genetics Female Gene Expression Regulation, Neoplastic / drug effects Humans MCF-7 Cells Nanog Homeobox Protein / genetics Nodal Protein / genetics Phosphorylation / drug effects Protein Biosynthesis / genetics RNA Isoforms / genetics Snail Family Transcription Factors / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
19 05 2020
Historique:
received: 20 03 2019
accepted: 27 04 2020
entrez: 20 5 2020
pubmed: 20 5 2020
medline: 11 8 2020
Statut: epublish

Résumé

Plasticity of neoplasia, whereby cancer cells attain stem-cell-like properties, is required for disease progression and represents a major therapeutic challenge. We report that in breast cancer cells NANOG, SNAIL and NODAL transcripts manifest multiple isoforms characterized by different 5' Untranslated Regions (5'UTRs), whereby translation of a subset of these isoforms is stimulated under hypoxia. The accumulation of the corresponding proteins induces plasticity and "fate-switching" toward stem cell-like phenotypes. Mechanistically, we observe that mTOR inhibitors and chemotherapeutics induce translational activation of a subset of NANOG, SNAIL and NODAL mRNA isoforms akin to hypoxia, engendering stem-cell-like phenotypes. These effects are overcome with drugs that antagonize translational reprogramming caused by eIF2α phosphorylation (e.g. ISRIB), suggesting that the Integrated Stress Response drives breast cancer plasticity. Collectively, our findings reveal a mechanism of induction of plasticity of breast cancer cells and provide a molecular basis for therapeutic strategies aimed at overcoming drug resistance and abrogating metastasis.

Identifiants

DOI: 10.1038/s41467-020-16352-z PMID: 32427827 PMC: PMC7237473
pubmed: 32427827
doi: 10.1038/s41467-020-16352-z
pii: 10.1038/s41467-020-16352-z
pmc: PMC7237473
doi:

Substances chimiques

5' Untranslated Regions 0
Antineoplastic Agents 0
Eukaryotic Initiation Factor-2 0
Nanog Homeobox Protein 0
Nodal Protein 0
RNA Isoforms 0
SNAI1 protein, human 0
Snail Family Transcription Factors 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2498

Subventions

Organisme : NIDDK NIH HHS
ID : R01 DK053307
Pays : United States
Organisme : CIHR
ID : PLS 9538
Pays : Canada
Organisme : CIHR
ID : PLS 95381
Pays : Canada
Organisme : CIHR
ID : MOP 38160
Pays : Canada
Organisme : NIDDK NIH HHS
ID : R37 DK060596
Pays : United States

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Auteurs

Michael Jewer (M)

Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada.
Department of Oncology, University of Alberta, Edmonton, AB, Canada.

Laura Lee (L)

Department of Oncology, University of Alberta, Edmonton, AB, Canada.

Matthew Leibovitch (M)

Lady Davis Institute, Departments of Oncology and Biochemistry, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.

Guihua Zhang (G)

Department of Oncology, University of Alberta, Edmonton, AB, Canada.

Jiahui Liu (J)

Department of Oncology, University of Alberta, Edmonton, AB, Canada.

Scott D Findlay (SD)

Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada.
Department of Oncology, University of Alberta, Edmonton, AB, Canada.

Krista M Vincent (KM)

Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada.
Department of Oncology, University of Alberta, Edmonton, AB, Canada.

Kristofferson Tandoc (K)

Lady Davis Institute, Departments of Oncology and Biochemistry, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.

Dylan Dieters-Castator (D)

Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada.

Daniela F Quail (DF)

Goodman Cancer Center, McGill University, Montreal, QC, Canada.
ORCID: 0000-0002-6969-3250

Indrani Dutta (I)

Department of Oncology, University of Alberta, Edmonton, AB, Canada.

Mackenzie Coatham (M)

Department of Oncology, University of Alberta, Edmonton, AB, Canada.

Zhihua Xu (Z)

Department of Oncology, University of Alberta, Edmonton, AB, Canada.

Aakshi Puri (A)

Lady Davis Institute, Departments of Oncology and Biochemistry, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.

Bo-Jhih Guan (BJ)

Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.

Maria Hatzoglou (M)

Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.

Andrea Brumwell (A)

Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.

James Uniacke (J)

Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
ORCID: 0000-0001-9632-4277

Christos Patsis (C)

Lady Davis Institute, Departments of Oncology and Biochemistry, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.

Antonis Koromilas (A)

Lady Davis Institute, Departments of Oncology and Biochemistry, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.

Julia Schueler (J)

Charles River Discovery Research Services Germany, Freiburg, Germany.
ORCID: 0000-0003-1984-7343

Gabrielle M Siegers (GM)

Department of Oncology, University of Alberta, Edmonton, AB, Canada.
ORCID: 0000-0003-2154-0279

Ivan Topisirovic (I)

Lady Davis Institute, Departments of Oncology and Biochemistry, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
ORCID: 0000-0002-5510-9762

Lynne-Marie Postovit (LM)

Department of Oncology, University of Alberta, Edmonton, AB, Canada. l.postovit@queensu.ca.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada. l.postovit@queensu.ca.
ORCID: 0000-0002-8088-4197

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Régions non traduites › Régions 5' non traduites › Translational control of breast cancer plasticity.
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Translational control of breast cancer plasticity.
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › Translational control of breast cancer plasticity.
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Respiration cellulaire › Hypoxie cellulaire › Translational control of breast cancer plasticity.
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Translational control of breast cancer plasticity.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines ribosomiques › Facteurs initiation chaîne peptidique › Facteurs d'initiation eucaryotes › Facteur-2 d'initiation eucaryote › Translational control of breast cancer plasticity.
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Translational control of breast cancer plasticity.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Translational control of breast cancer plasticity.
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › Cellules MCF-7 › Translational control of breast cancer plasticity.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéine homéotique Nanog › Translational control of breast cancer plasticity.
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines de la superfamille du TGF bêta › Ligands de la voie de signalisation Nodal › Protéine Nodal › Translational control of breast cancer plasticity.
questionsmedicales.fr › Métabolisme › Phosphorylation › Translational control of breast cancer plasticity.
questionsmedicales.fr › Phénomènes génétiques › Expression des gènes › Biosynthèse des protéines › Translational control of breast cancer plasticity.
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › Isoformes d'ARN › Translational control of breast cancer plasticity.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription de la famille Snail › Translational control of breast cancer plasticity.