Translational Regulation of Cancer Metastasis

Abstract

Deregulation of the mRNA translational process has been observed during tumorigenesis. However, recent findings have shown that deregulation of translation also contributes specifically to cancer cell spread. During metastasis, cancer cells undergo changes in cellular state, permitting the acquisition of features necessary for cell survival, dissemination, and outgrowth. In addition, metastatic cells respond to external cues, allowing for their persistence under significant cellular and microenvironmental stresses. Recent work has revealed the importance of mRNA translation to these dynamic changes, including regulation of cell states through epithelial-to-mesenchymal transition and tumor dormancy and as a response to external stresses such as hypoxia and immune surveillance. In this review, we focus on examples of altered translation underlying these phenotypic changes and responses to external cues and explore how they contribute to metastatic progression. We also highlight the therapeutic opportunities presented by aberrant mRNA translation, suggesting novel ways to target metastatic tumor cells.

Figure 1:

Dysregulation of translation initiation during cancer. Ribosome biogenesis includes the coordinated assembly of ribosomal proteins and rRNA to form the 40S and 60S ribosomal subunits. This process is, in part, regulated by Myc and mTOR, which are frequently aberrantly activated in cancer. Translation initiation occurs by two distinct mechanisms: cap-dependent translation and cap-independent translation. In cap-dependent translation, the initiation factors eIF4A, eIF4E, and eIF4G bind to the 5’ cap of mRNA transcripts, with subsequent recruitment of the 40S subunit. eIF4E and eIF4G are frequently amplified in cancer, and other oncogenes, including Myc and mTOR, also activate translation initiation. In cap-independent translation, an internal ribosome entry site (IRES) recruits the 40S ribosome without the initiation factors. This method of translational initiation is prevalent in situations of cellular stress, including hypoxia and oxidative stress. In both mechanisms of translational initiation, the 40S subunits scans the transcript for an AUG start site, at which point eIF2 is released, the 60S ribosome is recruited to form the full 80S ribosome, and translation elongation begins.

Figure 2:

Therapeutic vulnerabilities based on translational aberrations in tumor cells progressing through the metastatic cascade. (A) Primary tumor cells activate mTOR and other translational pathways to induce epithelial plasticity, promoting escape from primary tumors and intravasation into the circulation. (B) Circulating tumor cells (CTCs) and CTC clusters with increased metastatic capacity exhibit upregulation of translational machinery. Neutrophils dependent on translation interact with CTCs to facilitate CTC extravasation. (C) Disseminated tumor cells (DTCs) translationally regulate surface expression of the immunosuppressive ligand PD-L1, promoting immune evasion. (D) Growing metastases activate mTOR and proliferation pathways, and mTOR inhibitors are approved for use in metastatic breast, renal and neuroendocrine cancers. In each panel, therapies targeting protein translation with efficacy in metastasis models or in metastatic cancer patients are highlighted.