Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis.

Abstract

Circulating tumor cells (CTCs) are shed into the bloodstream from primary tumors, but only a small subset of these cells generates metastases. We conducted an in vivo genome-wide CRISPR activation screen in CTCs from breast cancer patients to identify genes that promote distant metastasis in mice. Genes coding for ribosomal proteins and regulators of translation were enriched in this screen. Overexpression of RPL15, which encodes a component of the large ribosomal subunit, increased metastatic growth in multiple organs and selectively enhanced translation of other ribosomal proteins and cell cycle regulators. RNA sequencing of freshly isolated CTCs from breast cancer patients revealed a subset with strong ribosome and protein synthesis signatures; these CTCs expressed proliferation and epithelial markers and correlated with poor clinical outcome. Therapies targeting this aggressive subset of CTCs may merit exploration as potential suppressors of metastatic progression.

• Authors: Richard Y Ebright, Sooncheol Lee, Ben S Wittner, Kira L Niederhoffer, Benjamin T Nicholson, Aditya Bardia, Samuel Truesdell, Devon F Wiley, Benjamin Wesley, Selena Li, Andy Mai, Nicola Aceto, Nicole Vincent-Jordan, Annamaria Szabolcs, Brian Chirn, Johannes Kreuzer, Valentine Comaills, Mark Kalinich, Wilhelm Haas, David T Ting, Mehmet Toner, Shobha Vasudevan, Daniel A Haber, Shyamala Maheswaran, Douglas S Micalizzi
• Journal: Science (New York, N.Y.) (Science) Vol. 367 Issue 6485 Pg. 1468-1473 (03 27 2020) ISSN: 1095-9203 [Electronic] United States
• PMID: 32029688 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Ribosomal Proteins

Topics

• Animals
• Breast Neoplasms (genetics, pathology)
• CRISPR-Cas Systems
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Neoplasm Metastasis
• Neoplasm Transplantation
• Neoplastic Cells, Circulating (pathology)
• Ribosomal Proteins (genetics)
• Sequence Analysis, RNA