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

Matthew J. Regner, Kamila Wisniewska, Susana Garcia-Recio, Aatish Thennavan, Raul Mendez-Giraldez, Venkat S. Malladi, Gabrielle Hawkins, Joel S. Parker, Charles M. Perou, Victoria L. Bae-Jump, Hector L. Franco

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4924-4941.e10
JournalMolecular cell
Volume81
Issue number23
DOIs
StatePublished - Dec 2 2021
Externally publishedYes

Keywords

  • chromatin accessibility
  • endometrial cancer
  • enhancer elements
  • gastro-intestinal stromal tumors
  • gene regulation
  • intratumoral heterogeneity
  • ovarian cancer
  • scATAC-seq
  • scRNA-seq
  • single-cell genomics

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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