Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma

  1. Wayne Croft
  2. Hayden Pearce
  3. Sandra Margielewska-Davies
  4. Lindsay Lim
  5. Samantha M Nicol
  6. Fouzia Zayou
  7. Daniel Blakeway
  8. Francesca Marcon
  9. Sarah Powell-Brett
  10. Brinder Mahon
  11. Reena Merard
  12. Jianmin Zuo
  13. Gary Middleton
  14. Keith Roberts
  15. Rachel M Brown
  16. Paul Moss  Is a corresponding author
  1. University of Birmingham, United Kingdom
  2. The Francis Crick Institute, United Kingdom
  3. University Hospitals Birmingham NHS Foundation Trust, United Kingdom

Abstract

Pancreatic ductal adenocarcinoma has a poor clinical outcome and responses to immunotherapy are suboptimal. Stromal fibroblasts are a dominant but heterogenous population within the tumor microenvironment and therapeutic targeting of stromal subsets may have therapeutic utility. Here we combine spatial transcriptomics and scRNA-Seq datasets to define the transcriptome of tumor-proximal and tumor-distal cancer-associated fibroblasts (CAFs) and link this to clinical outcome. Tumor-proximal fibroblasts comprise large populations of myofibroblasts, strongly expressed podoplanin, and were enriched for Wnt ligand signaling. In contrast, inflammatory CAFs were dominant within tumor-distal subsets and expressed complement components and the Wnt-inhibitor SFRP2. Poor clinical outcome was correlated with elevated HIF-1a and podoplanin expression whilst expression of inflammatory and complement genes was predictive of extended survival. These findings demonstrate the extreme transcriptional heterogeneity of CAFs and its determination by apposition to tumor. Selective targeting of tumor-proximal subsets, potentially combined with HIF-1a inhibition and immune stimulation, may offer a multi-modal therapeutic approach for this disease.

Data availability

Source Data 1 contains the raw Nanostring nCounter data.

The following previously published data sets were used

Article and author information

Author details

  1. Wayne Croft

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6780-5944
  2. Hayden Pearce

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Sandra Margielewska-Davies

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5115-470X
  4. Lindsay Lim

    Cancer Research Horizons, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1394-3297
  5. Samantha M Nicol

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Fouzia Zayou

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Daniel Blakeway

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9501-7451
  8. Francesca Marcon

    University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7439-8291
  9. Sarah Powell-Brett

    University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Brinder Mahon

    University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Reena Merard

    University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Jianmin Zuo

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Gary Middleton

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Keith Roberts

    University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Rachel M Brown

    University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Paul Moss

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    For correspondence
    p.moss@bham.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6895-1967

Funding

Cancer Research UK (A21135)

  • Wayne Croft
  • Hayden Pearce
  • Sandra Margielewska-Davies
  • Lindsay Lim
  • Samantha M Nicol
  • Fouzia Zayou
  • Daniel Blakeway
  • Francesca Marcon
  • Sarah Powell-Brett
  • Brinder Mahon
  • Reena Merard
  • Jianmin Zuo
  • Gary Middleton
  • Keith Roberts
  • Rachel M Brown
  • Paul Moss

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kay F Macleod, University of Chicago, United States

Ethics

Human subjects: Samples were obtained from the Birmingham Human Biomaterials Resource Centre HBRC (HTA Licence 12358) ethically approved North West - Haydock Research Ethics Committee; Ref 20/NW/0001, local ethics number 18-304.

Version history

  1. Received: January 11, 2023
  2. Preprint posted: January 21, 2023 (view preprint)
  3. Accepted: June 22, 2023
  4. Accepted Manuscript published: June 23, 2023 (version 1)
  5. Version of Record published: July 21, 2023 (version 2)

Copyright

© 2023, Croft et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Wayne Croft
  2. Hayden Pearce
  3. Sandra Margielewska-Davies
  4. Lindsay Lim
  5. Samantha M Nicol
  6. Fouzia Zayou
  7. Daniel Blakeway
  8. Francesca Marcon
  9. Sarah Powell-Brett
  10. Brinder Mahon
  11. Reena Merard
  12. Jianmin Zuo
  13. Gary Middleton
  14. Keith Roberts
  15. Rachel M Brown
  16. Paul Moss
(2023)
Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma
eLife 12:e86125.
https://doi.org/10.7554/eLife.86125

Share this article

https://doi.org/10.7554/eLife.86125

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