Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma
- University of Birmingham, United Kingdom
- The Francis Crick Institute, United Kingdom
- 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.
Article and author information
Author details
Sandra Margielewska-Davies
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
- 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
- Received: January 11, 2023
- Preprint posted: January 21, 2023 (view preprint)
- Accepted: June 22, 2023
- Accepted Manuscript published: June 23, 2023 (version 1)
- 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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Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma
eLife 12:e86125.
https://doi.org/10.7554/eLife.86125
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