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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-06-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/86125 |
| _version_ | 1797775517621944320 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Wayne Croft |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-12T22:37:50Z |
| format | Article |
| id | doaj.art-d7357419260341daa6df22adc8ce75ad |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-12T22:37:50Z |
| publishDate | 2023-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d7357419260341daa6df22adc8ce75ad2023-07-21T11:45:10ZengeLife Sciences Publications LtdeLife2050-084X2023-06-011210.7554/eLife.86125Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinomaWayne Croft0https://orcid.org/0000-0001-6780-5944Hayden Pearce1https://orcid.org/0000-0002-8380-8122Sandra Margielewska-Davies2https://orcid.org/0000-0002-5115-470XLindsay Lim3https://orcid.org/0000-0003-1394-3297Samantha M Nicol4Fouzia Zayou5Daniel Blakeway6https://orcid.org/0000-0001-9501-7451Francesca Marcon7https://orcid.org/0000-0001-7439-8291Sarah Powell-Brett8Brinder Mahon9Reena Merard10Jianmin Zuo11Gary Middleton12Keith Roberts13Rachel M Brown14Paul Moss15https://orcid.org/0000-0002-6895-1967Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre for Computational Biology, University of Birmingham, Birmingham, United KingdomInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomCancer Research Horizons, The Francis Crick Institute, London, United KingdomInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomUniversity Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, United KingdomUniversity Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, United KingdomUniversity Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, United KingdomUniversity Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, United KingdomInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United KingdomInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, United KingdomUniversity Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, United KingdomUniversity Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, United KingdomInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, United KingdomPancreatic 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.https://elifesciences.org/articles/86125pancreatic cancerPDACcancer-associated fibroblastsNanoString GeoMxtumour microenvironment |
| spellingShingle | 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 Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma eLife pancreatic cancer PDAC cancer-associated fibroblasts NanoString GeoMx tumour microenvironment |
| 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 | pancreatic cancer PDAC cancer-associated fibroblasts NanoString GeoMx tumour microenvironment |
| url | https://elifesciences.org/articles/86125 |
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