Nearly ninety per cent of all cancer patient deaths are due to metastasis. A study shows that a process that allows the cells to metastasize is aided by the synthesis of new ribosomes, the cell components in which proteins are produced. The results open the possibility for new treatment strategies for advanced cancers. The study is published in Nature Communications.
As tumors progress towards advanced stages they dedifferentiate, become more aggressive and lose the characteristics of the origin tissue. They also acquire the migratory capacity that allows the tumor to spread or metastasize to distant sites in the body, eventually causing patient death.
For epithelial tumors to metastasize the tumor cells undergo a process known as the epithelial-to-mesenchymal transition (EMT), which allows the cells to develop migratory ability. During EMT, cells also lose their proliferative capacity and become more stem-like. This remarkable transition leads to both increased invasiveness and an ability to evade numerous cancer treatments including hormonal therapies.
In the present study the researchers found that EMT is aided by the synthesis of new ribosomes, which serve to synthesize the proteins required for cell functions. Their study therefore argues that ribosome biogenesis may be more than just a pro-proliferative process.
"Until recently, ribosomes have been considered to play only passive roles during the production of proteins. Our study shows that ribosomes potentially have complex, active roles and suggests that more attention should be given to understanding how ribosomes contribute to cell physiology in health and disease states," says the study lead.
This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF).EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2).
The researchers also demonstrated that by inhibiting the formation of new ribosomes, aggressive and hormone insensitive tumors could be partially reverted to a benign and non-metastatic type. Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ERα) positive, Rictor-negative phenotype and reduces metastasis.
"We used a small molecule called CX-5461 to inhibit ribosome biogenesis in mouse models of human tumors. We found that primary tumors reverted from an invasive type to a non-invasive type as well as potentially regaining sensitivity to hormonal therapy. Importantly, CX-5461 treatment also resulted in a marked reduction of number lung metastases. This suggests that treatment with CX-5461 may enhance hormone therapy responsiveness in patients where this kind of treatment doesn't work any more. We find this to be a remarkable breakthrough and we are currently pursuing a number of additional validation studies," says the lead.
Epithelial to mesenchymal transition (EMT) require ribosomal synthesis in cancer
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