Cell
Volume 178, Issue 1, 27 June 2019, Pages 160-175.e27
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Article
Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer

https://doi.org/10.1016/j.cell.2019.05.012Get rights and content
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Highlights

  • Cancer-associated fibroblasts contribute to pancreatic cancer heterogeneity

  • Cancer cells can have a double-positive phenotype: proliferation and invasion

  • High CAF abundance linked with DP cells enriched for MAPK and STAT3 co-signaling

  • Intra-tumoral gland types provide tissue heterogeneity linked with clinical outcome

Summary

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

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

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These authors contributed equally

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