Genome-wide CRISPR screen identifies PRC2 and KMT2D-COMPASS as regulators of distinct EMT trajectories that contribute differentially to metastasis

Yun Zhang*, Joana Liu Donaher, Sunny Das, Xin Li, Ferenc Reinhardt, Jordan A. Krall, Arthur W. Lambert, Prathapan Thiru, Heather R. Keys, Mehreen Khan, Matan Hofree, Molly M. Wilson, Ozlem Yedier-Bayram, Nathan A. Lack, Tamer T. Onder, Tugba Bagci-Onder, Michael Tyler, Itay Tirosh, Aviv Regev, Jacqueline A. LeesRobert A. Weinberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Epithelial–mesenchymal transition (EMT) programs operate within carcinoma cells, where they generate phenotypes associated with malignant progression. In their various manifestations, EMT programs enable epithelial cells to enter into a series of intermediate states arrayed along the E–M phenotypic spectrum. At present, we lack a coherent understanding of how carcinoma cells control their entrance into and continued residence in these various states, and which of these states favour the process of metastasis. Here we characterize a layer of EMT-regulating machinery that governs E–M plasticity (EMP). This machinery consists of two chromatin-modifying complexes, PRC2 and KMT2D-COMPASS, which operate as critical regulators to maintain a stable epithelial state. Interestingly, loss of these two complexes unlocks two distinct EMT trajectories. Dysfunction of PRC2, but not KMT2D-COMPASS, yields a quasi-mesenchymal state that is associated with highly metastatic capabilities and poor survival of patients with breast cancer, suggesting that great caution should be applied when PRC2 inhibitors are evaluated clinically in certain patient cohorts. These observations identify epigenetic factors that regulate EMP, determine specific intermediate EMT states and, as a direct consequence, govern the metastatic ability of carcinoma cells.

Original languageAmerican English
Pages (from-to)554-564
Number of pages11
JournalNature Cell Biology
Volume24
Issue number4
DOIs
StatePublished - Apr 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

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