Translational control of breast cancer plasticity.

Zhihua Xu, Lynne-Marie Postovit, Ivan Topisirovic, Gabrielle M Siegers, Julia Schueler, Antonis Koromilas, Christos Patsis, James Uniacke, Andrea Brumwell, Maria Hatzoglou, Bo-Jhih Guan, Aakshi Puri, Michael Jewer, Mackenzie Coatham, Indrani Dutta, Daniela F Quail, Dylan Dieters-Castator, Kristofferson Tandoc, Krista M Vincent, Scott D Findlay, Jiahui Liu, Guihua Zhang, Matthew Leibovitch, Laura Lee

Journal: Nature communications 2020;11(1):2498

PMID: 32427827

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Abstract

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.

Address: Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada.; Department of Oncology, University of Alberta, Edmonton, AB, Canada.; Lady Davis Institute, Departments of Oncology and Biochemistry, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.; Goodman Cancer Center, McGill University, Montreal, QC, Canada.; Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.; Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.; Charles River Discovery Research Services Germany, Freiburg, Germany.; Department of Oncology, University of Alberta, Edmonton, AB, Canada. [email protected].; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada. [email protected].

DOI: 10.1038/s41467-020-16352-z