Reprogramming lineage features promotes epithelial behavior in carcinoma cells

Cancer cells distort epigenetic control of gene expression, allowing for a remarkable degree of plasticity and loss of cell type identity. At the same time, expression of identity-discordant lineage determinants can significantly shift cell phenotype by creating lineage hybrid states. One example is the misexpression of IKZF3, encoding the lymphocyte restricted transcription factor Aiolos, by roughly half of non-small cell lung carcinomas (NSCLC) and the majority of small cell lung carcinomas [1]. During normal lymphocyte development, pre-B progenitors enter a proliferative phase dependent on survival cues from bone marrow stroma. To progress, Aiolos and its paralog Ikaros (IKZF1) repress multiple adhesion-related genes, releasing cells from this epithelial-type dependence on solid matrix in preparation for their release as mature lymphocytes into the circulation [2, 3]. In lung cancers, unlicensed expression of Aiolos initiates a similar shift from an epithelial to a lymphocyte-like state by repression of multiple adhesion-related genes, resulting in loss of anoikis and consequent metastatic spread [1]. To reverse these lymphoid traits, we created a chimeric epigenetic editor designed to specifically retrieve Aiolos-repressed epithelial adhesion properties. Here, we demonstrate proof of principle for epithelial lineage restoration by exploiting a lymphocyte developmental pathway.