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Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma
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 spa...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361717/ https://www.ncbi.nlm.nih.gov/pubmed/37350578 http://dx.doi.org/10.7554/eLife.86125 |
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author | Croft, Wayne Pearce, Hayden Margielewska-Davies, Sandra Lim, Lindsay Nicol, Samantha M Zayou, Fouzia Blakeway, Daniel Marcon, Francesca Powell-Brett, Sarah Mahon, Brinder Merard, Reena Zuo, Jianmin Middleton, Gary Roberts, Keith Brown, Rachel M Moss, Paul |
author_facet | Croft, Wayne Pearce, Hayden Margielewska-Davies, Sandra Lim, Lindsay Nicol, Samantha M Zayou, Fouzia Blakeway, Daniel Marcon, Francesca Powell-Brett, Sarah Mahon, Brinder Merard, Reena Zuo, Jianmin Middleton, Gary Roberts, Keith Brown, Rachel M Moss, Paul |
author_sort | Croft, Wayne |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10361717 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-103617172023-07-22 Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma Croft, Wayne Pearce, Hayden Margielewska-Davies, Sandra Lim, Lindsay Nicol, Samantha M Zayou, Fouzia Blakeway, Daniel Marcon, Francesca Powell-Brett, Sarah Mahon, Brinder Merard, Reena Zuo, Jianmin Middleton, Gary Roberts, Keith Brown, Rachel M Moss, Paul eLife Cancer Biology 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. eLife Sciences Publications, Ltd 2023-06-23 /pmc/articles/PMC10361717/ /pubmed/37350578 http://dx.doi.org/10.7554/eLife.86125 Text en © 2023, Croft, Pearce et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology Croft, Wayne Pearce, Hayden Margielewska-Davies, Sandra Lim, Lindsay Nicol, Samantha M Zayou, Fouzia Blakeway, Daniel Marcon, Francesca Powell-Brett, Sarah Mahon, Brinder Merard, Reena Zuo, Jianmin Middleton, Gary Roberts, Keith Brown, Rachel M Moss, Paul Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma |
title | Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma |
title_full | Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma |
title_fullStr | Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma |
title_full_unstemmed | Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma |
title_short | Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma |
title_sort | spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361717/ https://www.ncbi.nlm.nih.gov/pubmed/37350578 http://dx.doi.org/10.7554/eLife.86125 |
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