Translational control of breast cancer plasticity

Michael Jewer, Laura Lee, Matthew Leibovitch, Guihua Zhang, Jiahui Liu, Scott D. Findlay, Krista M. Vincent, Kristofferson Tandoc, Dylan Dieters-Castator, Daniela F. Quail, Indrani Dutta, Mackenzie Coatham, Zhihua Xu, Aakshi Puri, Bo-Jhih Guan, Maria Hatzoglou, Andrea Brumwell, James Uniacke, Christos Patsis, Antonis Koromilas, Julia Schueler, Gabrielle M. Siegers, Ivan Topisirovic and Lynne-Marie Postovit ()
Additional contact information
Michael Jewer: University of Western Ontario
Laura Lee: University of Alberta
Matthew Leibovitch: McGill University
Guihua Zhang: University of Alberta
Jiahui Liu: University of Alberta
Scott D. Findlay: University of Western Ontario
Krista M. Vincent: University of Western Ontario
Kristofferson Tandoc: McGill University
Dylan Dieters-Castator: University of Western Ontario
Daniela F. Quail: McGill University
Indrani Dutta: University of Alberta
Mackenzie Coatham: University of Alberta
Zhihua Xu: University of Alberta
Aakshi Puri: McGill University
Bo-Jhih Guan: Case Western Reserve University
Maria Hatzoglou: Case Western Reserve University
Andrea Brumwell: University of Guelph
James Uniacke: University of Guelph
Christos Patsis: McGill University
Antonis Koromilas: McGill University
Julia Schueler: Charles River Discovery Research Services Germany
Gabrielle M. Siegers: University of Alberta
Ivan Topisirovic: McGill University
Lynne-Marie Postovit: University of Alberta

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16352-z

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