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Cancer evolution constitutes a foremost obstacle to effective treatment, driving malignant cells to adapt and overcome therapy. We hypothesize that both genetic and epigenetic determinants govern the biology of key cellular states that drive gliomas and their plasticity, calling for an integrative model of cancer evolution, encompassing both genetic and epigenetic sources of heritable variations within tumors. To address this challenge, the Landau laboratory developed novel multi-omics single-cell sequencing technologies that enable direct integration across genetic, epigenetic, and cell state dimensions of cell-to-cell variation, and have applied them to study clonal evolution in hematological malignancies. In this Sontag funded project, we seek to apply this multi-layered single-cell approach to human gliomas in order to define how cellular plasticity (i.e., the ability to switch between cell states) and evolution enable tumor cell growth.