A multi-omic single-cell landscape of human gynecologic malignancies

Deconvolution of regulatory mechanisms that drive transcriptional programs in cancer cells is key to understanding tumor biology. Herein, we present matched transcriptome (scRNA-seq) and chromatin accessibility (scATAC-seq) profiles at single-cell resolution from human ovarian and endometrial tumors processed immediately following surgical resection. This dataset reveals the complex cellular heterogeneity of these tumors and enabled us to quantitatively link variation in chromatin accessibility to gene expression. We show that malignant cells acquire previously unannotated regulatory elements to drive hallmark cancer pathways. Moreover, malignant cells from within the same patients show substantial variation in chromatin accessibility linked to transcriptional output, highlighting the importance of intratumoral heterogeneity. Finally, we infer the malignant cell type-specific activity of transcription factors. By defining the regulatory logic of cancer cells, this work reveals an important reliance on oncogenic regulatory elements and highlights the ability of matched scRNA-seq/scATAC-seq to uncover clinically relevant mechanisms of tumorigenesis in gynecologic cancers. [Display omitted] •First matched scRNA-seq and scATAC-seq dataset of human gynecologic tumors•Rewiring of chromatin accessibility linked to transcriptional output in cancer cells•Identification of cancer-specific and clinically relevant distal regulatory elements•Differential transcription factor activity drives intratumor heterogeneity Regner, Wisniewska, et al. present an integrated analysis of single-cell transcriptomics and chromatin accessibility data to define the regulatory logic of malignant cell states in human gynecologic cancers. They identify thousands of salient cancer-specific distal regulatory elements and uncover differential transcription factor activity that drives intratumor heterogeneity.