Projects per year
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 language | English |
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Article number | 86125 |
Number of pages | 19 |
Journal | eLife |
Volume | 12 |
Early online date | 23 Jun 2023 |
DOIs | |
Publication status | Published - 21 Jul 2023 |
Keywords
- NanoString GeoMx
- cancer-associated fibroblasts
- PDAC
- tumour microenvironment
- Human
- pancreatic cancer
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Dive into the research topics of 'Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma'. Together they form a unique fingerprint.Projects
- 2 Finished
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PAVE - A nanovaccine Approach for the treatment of Pancreatic Cancer
Grand, R. (Researcher), Moss, P. (Principal Investigator) & Stewart, G. (Researcher)
1/10/19 → 31/03/24
Project: EU
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From immune suppression to immunotherapy: the function and clinical significance of the immune response to pancreatic cancer
Moss, P. (Principal Investigator), Middleton, G. (Co-Investigator) & Cazier, J.-B. (Co-Investigator)
1/07/16 → 31/01/23
Project: Research