Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-16352-z
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Funding
- Canadian Institutes for Health Research [PLS 9538, PLS 95381]
- Canadian Breast Cancer Foundation Prairies
- Alberta Cancer Foundation
- Women and Children's Health Research Institute
- Alberta Innovates Health Solutions
- Natural Sciences and Engineering Research Council of Canada
- Ontario Graduate Scholarship
- McGill Integrated Cancer Training Program
- AIHS
- CIHR [MOP 38160]
- Sawin-Baldwin Chair in Ovarian Cancer
- Dr. Anthony Noujaim Legacy Oncology Chair
- AIHS translational health chair in cancer
- Canadian Cancer Society Research Institute grant (CCSRI) [700886]
- Quebec Breast Cancer Foundation
- [R-37-DK060596]
- [R01-DK 053307]
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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 eIF2 alpha 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.
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