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.
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.
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
Further reading
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- Cancer Biology
Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca−/− KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.
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- Cancer Biology
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