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

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*, Tony Ng

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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-1α 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-1α inhibition and immune stimulation, may offer a multi-modal therapeutic approach for this disease.
Original languageEnglish
Article number86125
Number of pages19
JournaleLife
Volume12
Early online date23 Jun 2023
DOIs
Publication statusPublished - 21 Jul 2023

Keywords

  • NanoString GeoMx
  • cancer-associated fibroblasts
  • PDAC
  • tumour microenvironment
  • Human
  • pancreatic cancer

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