Single-cell transcriptomics identifies gene expression networks driving differentiation and tumorigenesis in the human fallopian tube

Cell Rep. 2021 Apr 13;35(2):108978. doi: 10.1016/j.celrep.2021.108978.

Abstract

The human fallopian tube harbors the cell of origin for the majority of high-grade serous "ovarian" cancers (HGSCs), but its cellular composition, particularly the epithelial component, is poorly characterized. We perform single-cell transcriptomic profiling of around 53,000 individual cells from 12 primary fallopian specimens to map their major cell types. We identify 10 epithelial subpopulations with diverse transcriptional programs. Based on transcriptional signatures, we reconstruct a trajectory whereby secretory cells differentiate into ciliated cells via a RUNX3high intermediate. Computational deconvolution of advanced HGSCs identifies the "early secretory" population as a likely precursor state for the majority of HGSCs. Its signature comprises both epithelial and mesenchymal features and is enriched in mesenchymal-type HGSCs (p = 6.7 × 10-27), a group known to have particularly poor prognoses. This cellular and molecular compendium of the human fallopian tube in cancer-free women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia.

Keywords: PAX8; RUNX3; SOX17; ciliated epithelial cells; fallopian tube; microenvironment; ovarian cancer; scRNA-seq; secretory epithelial cells; transcription factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Differentiation
  • Cell Line, Tumor
  • Core Binding Factor Alpha 3 Subunit / genetics*
  • Core Binding Factor Alpha 3 Subunit / metabolism
  • Endometriosis / genetics*
  • Endometriosis / metabolism
  • Endometriosis / pathology
  • Endometriosis / surgery
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Epithelial-Mesenchymal Transition
  • Fallopian Tubes / metabolism
  • Fallopian Tubes / pathology
  • Fallopian Tubes / surgery
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Leiomyoma / genetics*
  • Leiomyoma / metabolism
  • Leiomyoma / pathology
  • Leiomyoma / surgery
  • Middle Aged
  • PAX8 Transcription Factor / genetics*
  • PAX8 Transcription Factor / metabolism
  • SOXF Transcription Factors / genetics*
  • SOXF Transcription Factors / metabolism
  • Signal Transduction
  • Single-Cell Analysis
  • Transcriptome*

Substances

  • Core Binding Factor Alpha 3 Subunit
  • PAX8 Transcription Factor
  • PAX8 protein, human
  • Runx3 protein, human
  • SOX17 protein, human
  • SOXF Transcription Factors