Translational control of breast cancer plasticity

Jewer, M.; Lee, L.; Zhang, G.; Liu, J.; Findlay, S. D.; Vincent, K. M.; Tandoc, K.; Dieters-Castator, D.; Quail, D. F.; Dutta, I.; Coatham, M.; Xu, Z.; Guan, B.-J.; Hatzoglou, M.; Brumwell, A.; Uniacke, J.; Patsis, C.; Koromilas, A.; Schueler, J.; Siegers, G. M.; Topisirovic, I.; Postovit, L.-M.

doi:10.1101/596544

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bioRxiv · 10.1101/596544

Translational control of breast cancer plasticity

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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 (5UTRs), whereby translation of a subset of these isoforms is stimulated under hypoxia. This leads to accumulation of corresponding proteins which induce plasticity and \"fate-switching\" toward stem-cell like phenotypes. Surprisingly, we observed 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. Strikingly, these effects can be overcome with drugs that antagonize translational reprogramming caused by eIF2 phosphorylation (e.g. ISRIB). Collectively, our findings unravel a hitherto unappreciated 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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Jewer, M., Lee, L., Zhang, G., Liu, J., Findlay, S. D., Vincent, K. M., Tandoc, K., Dieters-Castator, D., Quail, D. F., Dutta, I., Coatham, M., Xu, Z., Guan, B.-J., Hatzoglou, M., Brumwell, A., Uniacke, J., Patsis, C., Koromilas, A., Schueler, J., Siegers, G. M., Topisirovic, I., Postovit, L.-M.. 2019-04-02. Translational control of breast cancer plasticity. https://doi.org/10.1101/596544

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