Abstract PR05: Loss of PRC2 or KMT2D-COMPASS generates two quasi-mesenchymal cell states with distinct metastatic abilities

Abstract

Abstract The epithelial-mesenchymal transition (EMT) is a key cell-biological program enabling carcinoma cell phenotypic plasticity. Accumulating evidence suggests EMT programs do not operate as a stereotypical program that functions as a binary switch, shifting cells from an epithelial (E) to a mesenchymal (M) state. Instead, EMT programs generate cells that enter into a series of intermediate states arrayed along the E-M phenotypic spectrum. At present, we still lack a coherent understanding of how carcinoma cells control their entrance into and residence in these various intermediate states, and which EMT intermediate state(s) favour the metastatic process. Here we characterize a new level of regulation of EMT, consisting of two chromatin-modifying complexes, PRC2 and KMT2D-COMPASS, that function as critical regulators to maintain stable residence of both normal and neoplastic cells in an epithelial state via regulating the downstream response of EMT-inducing signals. Dysfunction of either of these two complexes causes cells that were previously stably ensconced in an epithelial state to lapse into two distinct quasi-mesenchymal cell states with strongly differing metastatic abilities. These observations uncover a novel mechanism that regulates E-M plasticity, specifies which intermediate EMT state a cell will reside in, and thereby determines the metastatic ability of carcinoma cells. Citation Format: 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 Lees, Robert A. Weinberg. Loss of PRC2 or KMT2D-COMPASS generates two quasi-mesenchymal cell states with distinct metastatic abilities [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PR05.