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Micalizzi and graduate student Richard Ebright, who led the study, and their colleagues collected and analyzed CTCs from the blood of patients with metastatic hormone receptor-positive breast cancer and used cell lines generated from CTCs. They used CRISPR activation, a technique for studying the effect of gene activation, to screen the entire genome of the CTCs for genes that promote cancer spread.
They found that ribosomal proteins in general, and in particular one ribosomal protein, RPL15, promoted the spread of breast cancer and that patients with more aggressive breast cancer and worse survival tended to have CTCs with high levels of ribosomal proteins. In collaboration with the Vasudevan lab at MGH, they demonstrated that RPL15 alters the landscape of protein production within the CTCs.
Using a mouse model of metastatic breast cancer , the investigators tested the combination of targeted therapies consisting of an inhibitor of the ribosome and an inhibitor of cancer cell growth. They found that the combination had "dramatically increased efficacy " against RPL15 CTCs compared with other CTCs.These findings suggest that metastases might be slowed or prevented and warrants further investigation.
"These early results suggest that simultaneous therapeutic targeting of the cell translational machinery and cell proliferation pathways may merit investigation as a method to suppress an aggressive subset of CTCs that are characterized by high expression of RP genes," they write. Source:
Massachusetts General Hospital Journal reference:
Ebright, R.Y., et al. (2020) Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis. Science . doi.org/10.1126/science.aay0939 .
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