Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer

Cell. 2019 Jun 27;178(1):160-175.e27. doi: 10.1016/j.cell.2019.05.012. Epub 2019 May 30.

Abstract

Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenchymal transition (EMT) and proliferative (PRO) phenotypes linked with mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling. Using high-content digital imaging of RNA in situ hybridization in 195 PDAC tumors, we quantified these EMT and PRO subpopulations in 319,626 individual cancer cells that can be classified within the context of distinct tumor gland "units." Tumor gland typing provided an additional layer of intratumoral heterogeneity that was associated with differences in stromal abundance and clinical outcomes. This demonstrates the impact of the stroma in shaping tumor architecture by altering inherent patterns of tumor glands in human PDAC.

Keywords: mass spectrometry; pancreatic cancer; pancreatic ductal adenocarcinoma; single cell RNA-sequencing; single cell spatial analysis; stromal microenvironment; tumor architecture.

Publication types

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

MeSH terms

  • Animals
  • Cancer-Associated Fibroblasts / metabolism*
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Proliferation
  • Coculture Techniques
  • Epithelial-Mesenchymal Transition
  • Female
  • HEK293 Cells
  • Heterografts
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mitogen-Activated Protein Kinases / metabolism
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • RNA-Seq
  • STAT3 Transcription Factor / metabolism
  • Stromal Cells / metabolism
  • Transfection
  • Tumor Microenvironment*

Substances

  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Mitogen-Activated Protein Kinases