Science. 2020 Mar 27;367(6485):1468-1473.
Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis.
Ebright RY, Lee S, Wittner BS, Niederhoffer KL, Nicholson BT, Bardia A, Truesdell S, Wiley DF, Wesley B, Li S, Mai A, Aceto N, Vincent-Jordan N, Szabolcs A, Chirn B, Kreuzer J, Comaills V, Kalinich M, Haas W, Ting DT, Toner M, Vasudevan S, Haber DA, Maheswaran S, Micalizzi DS.
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Shriners Hospital for Children, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.
Metastasis: A matter of translation? Solid tumors shed a small number of cancer cells into the bloodstream, some of which are believed to contribute to metastasis. The molecular features that confer these circulating tumor cells (CTCs) with metastatic potential are poorly understood. Ebright et al. studied CTCs from breast cancer patients and found that cells with increased expression levels of certain ribosomal proteins and regulators of translation had greater metastatic capacity in a mouse model (see the Perspective by Ma and Jeffrey). Consistent with this finding, patients with higher levels of this subset of CTCs tended to have a poorer prognosis.
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.
Science. 2020 Mar 27;367(6485):1424-1425.
Deciphering cancer clues from blood.
Ning Ma, Stefanie S. Jeffrey.
Stanford University School of Medicine, Stanford, CA, USA.
Cancer is associated with considerable morbidity and mortality, and despite therapeutic advances, it still represents the second leading cause of death worldwide. As cancers grow, evolve, and spread, they shed circulating tumor cells (CTCs), as well as other tumor-associated cells and products, into the bloodstream. Capturing and analyzing CTCs or other tumor-associated cells and products from a patient's blood sample can provide insight into a particular cancer's biology, response to treatment, and/ or potential therapeutic targets. CTCs are heterogeneous; a pressing question concerns which CTCs represent those directly involved in metastasis, the major cause of cancer-related death. On page 1468 of this issue, Ebright et al. identify genes in patient-derived CTCs encoding ribosomal proteins (RPs) that were associated with metastatic progression in mouse models, poor outcome in patients, and alterations in global translation. These findings could point to potential biomarkers or targets for future metastatic cancer therapies.