Research ArticleCancer

Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis

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Science Translational Medicine  16 May 2018:
Vol. 10, Issue 441, eaap8307
DOI: 10.1126/scitranslmed.aap8307

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Blocking metastasis from the inside

Metastasis, the spread of tumor cells that often results in cancer patients’ deaths, remains difficult to treat for all cancer types. To intervene with this process, Frankowski et al. searched for inhibitors of the perinucleolar compartment, a structure located within the nuclei of cancer cells and associated with metastatic capacity. Through high-throughput screening followed by chemical optimization, the authors developed a compound they called metarrestin, which disrupts the perinuclear compartment in different types of cancer cells. They discovered that metarrestin inhibited tumor invasion and metastasis in multiple mouse models of cancer and prolonged the animals’ survival, suggesting its potential relevance for translation to patients.

Abstract

Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinuclear compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer.

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