Deciphering the COMPASS that guides cancer

forthcoming

Epigenetic features are commonly dysregulated in cancer and one of the surprising findings from the sequencing of cancer genomes is the high rate of alterations in many epigenetic regulators. KMT2D/MLL4, KMT2C/MLL3 and KDM6A/UTX are among the most frequently mutated genes in a wide range of cancers and in normal aged epithelial cells. Interestingly, these three genes are components of the same complex, COMPASS-like complex that regulate enhancer activity and regulate gene expression in a lineage specific manner. The deletion of members of the COMPASS-like complex has been associated with altered differentiation, aging and tumorigenesis. However, the precise mechanisms by which mutations in these genes impact cell states during tissue homeostasis, tumour initiation, tumour heterogeneity and metastasis, remain poorly understood. To address these important questions, we will use multidisciplinary approaches that will combine in vivo single cell lineage tracing, single-cell genomics, epigenomics and transcriptomics, in vivo CRISPR-based gene editing, together with genetic and pharmacologic perturbations, to define in a comprehensive and integrated manner the impact of Kmt2d, Kmt2c and Kdm6a deletion on cell state dynamics during homeostasis, regeneration, early steps of tumour initiation, tumour heterogeneity and metastasis in skin squamous cell carcinoma and bladder cancer. Moreover, we will perform genome wide CRISPR-Cas9 screen to identify the synthetically lethal genes in KMT2D, KMT2C and KDM6A mutated cancer cells to uncover new tumour vulnerabilities that can be pharmacologically targeted.