Epithelial mesenchymal transition mobilizes transposable genetic elements, drives genetic diversity and regulates expression of inflammatory genes in cancer cells

Faculty Development Competitive Research Grants 2020-2022

Epithelial mesenchymal transition (EMT) is a reversible embryonic genetic program activated in cancer cells and enhancing their metastatic potential. In embryonic development and in cancer, EMT programs are driven by the same transcription factors (so-called EMT-TFs). We characterized EMT-TF-induced alterations in histone modifications and associated changes in gene expression profiles in cancer cells. These unpublished data indicate that activation of EMT-TFs generates conditions permissive for the mobilization of transposable genetic elements (TE). Here, we formulate a hypothesis that EMT contributes to the genetic instability and tumour heterogeneity by mobilizing TE in the genomes of cancer cells. Current proposal is aiming to test this hypothesis. In addition, we will investigate the molecular mechanisms underlying the EMT-TF-activated pro-tumourigenic inflammatory response in cancer cells. We will investigate whether this activation is driven by TE mobilization and subsequent stimulation of the cGAS/STING (cyclic GMP-AMP synthase/STImulator of Interferon Genes) pathway, or achieved via a different mechanism. Overall, the proposed work will lead to the results important for the understanding of basic mechanisms of tumourigenesis. We will elucidate the links between EMT and genetic heterogeneity, and establish a causal relationship between EMT and secretion of inflammatory cytokines. The team of the investigators involved in the project includes the experts in EMT/cancer, chromatin/stem cell biology and bioinformatics/immunology. This composition of the team is ideal for the successful accomplishment of the objectives of this proposal.