Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Plasticity of neoplasia, whereby cancer cells attain stem-cell-like properties, is required for disease progression and represents a major therapeutic challenge.
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. Both processes require cancer cells to adapt to stresses like hypoxia or chemotherapy.
This adaptability can be mediated by increased plasticity of breast cancer cells enriching for breast cancer cells with stem-cell-like features BCSC 1 , 2. Hypoxia induces breast cancer cell plasticity and stem-cell-like phenotypes 3 , 4 , 5. Moreover, both stem-cell-like phenotypes and elevated expression of stemness-factors have been linked to metastatic spread and chemoresistance 1. Together, these pathways drive an adaptive stress response, conserving energy while enabling the expression of pro-survival factors, including ATF4 These studies show that translational reprograming may regulate stem-cell-associated plasticity, but the role of this process in the acquisition of BCSC phenotypes remains elusive.
This translationally induced stem cell program leads to the acquisition of BCSC phenotypes. Like hypoxia, mTOR inhibition and chemotherapeutics also induce plasticity via translational reprogramming.
Representative scatterplots defining CD44 and CD24 subpopulations. Hypoxia denoted in red and normoxia blue. Data represents independent experiments. Two-sided t -test for paired samples. Hypoxia is thought to increase the plasticity of cancer cells, enriching BCSC phenotypes. To evaluate translation, we employed polysome profiling, which separates efficiently versus inefficiently translated mRNAs by sucrose gradient ultracentrifugation Stresses like hypoxia cause adaptive translational reprogramming via modulating mTOR and ISR signaling 33 , 34 , 35 , VEGF protein was concurrently up-regulated Fig.
