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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
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.
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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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