A study co-led by Ludwig MIT Co-director Robert Weinberg employed a CRISPR screen to identify genes that control the plasticity of cells undergoing epithelial–mesenchymal transition (EMT), a complex gene expression program employed by settled cancer cells as they acquire the motility and invasiveness that allows them to metastasize. But the switch from the epithelial to mesenchymal state isn’t binary: EMT programs can induce a spectrum of cellular states between the two poles. Recent evidence suggests it is those in a “quasi-mesenchymal” state that are most likely to form metastatic outgrowths. Bob and his colleagues identified in an April paper in Nature Cell Biology two chromatin modifying complexes—PRC2 and KMT2D-COMPASS—that control EMT plasticity and have very different effects on cells. They show that loss of KMT2D-COMPASS pushes cells into a fully mesenchymal state, while PCR2 dysfunction pushes them into the middle state associated with enhanced metastasis. An examination of data from breast cancer patients showed that PRC2 loss is indeed associated with poor survival, supporting the hypothesis that the quasi-mesenchymal state is more conducive to metastasis. The findings have implications for therapies now under development that target PRC2 function, which in some types of cancers might promote metastasis—not quite the effect intended.
Read the study: Genome-wide CRISPR screen identifies PRC2 and KMT2D-COMPASS as regulators of distinct EMT trajectories that contribute differentially to metastasis, Nature Cell Biology, 2022 April 11 Epub
This article appeared in the September 2022 issue of Ludwig Link. Click here to download a PDF (1 MB).