Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis [rna-Seq BRx142]

We conducted an in vivo genome-wide CRISPR activation screen to identify genes that accelerate distal metastasis by breast cancer patient-derived circulating tumor cells (CTCs) following direct intravascular inoculation in mice. Regulators of translation and ribosomal proteins were prominent among these, and expression of RPL15, a component of the large ribosome subunit, was sufficient to increase metastatic growth in multiple organs. RPL15 overexpression selectively increases translation of other ribosomal proteins and cell cycle regulators. Unsupervised analysis of single-cell RNA sequencing of freshly-isolated CTCs from breast cancer patients identifies a subset with strong ribosomal and protein translation signatures, correlated with increased proliferative markers, epithelial markers and poor clinical outcome. Thus, ribosome protein expression identifies an aggressive subset of CTCs, whose therapeutic targeting may suppress metastatic progression. Overall design: We performed mRNA profiling in control and RPL15 overexpressing circulating tumor cell-derived cell lines to determine the translational efficiency for any given transcript (i.e., the ratio of ribosome-bound mRNA to all poly-A mRNA). Two control specimens and two RPL15 overexpressing specimens were profiled.