PLXDC1+ Tumor‐Associated Pancreatic Stellate Cells Promote Desmoplastic and Immunosuppressive Niche in Pancreatic Ductal Adenocarcinoma
Abstract Pancreatic stellate cells (PSCs) contribute to pancreatic ductal adenocarcinoma (PDAC) progression and therapeutic resistance, yet their detailed functions remain unclear. This study combined RNA sequencing and assay for transposase‐accessible chromatin using sequencing (ATAC‐seq) on sorted...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202415756 |
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| author | Yanhua Du Yizhou Zhao Judong Li Jiaxin Wang Shenglan You Yao Zhang Li Zhang Jihong Yang Hamid Alinejad‐Rokny Shujie Cheng Chenghao Shao Duowu Zou Youqiong Ye |
| author_facet | Yanhua Du Yizhou Zhao Judong Li Jiaxin Wang Shenglan You Yao Zhang Li Zhang Jihong Yang Hamid Alinejad‐Rokny Shujie Cheng Chenghao Shao Duowu Zou Youqiong Ye |
| author_sort | Yanhua Du |
| collection | DOAJ |
| description | Abstract Pancreatic stellate cells (PSCs) contribute to pancreatic ductal adenocarcinoma (PDAC) progression and therapeutic resistance, yet their detailed functions remain unclear. This study combined RNA sequencing and assay for transposase‐accessible chromatin using sequencing (ATAC‐seq) on sorted PSCs from adjacent normal and PDAC tissues to investigate their transcriptional and epigenetic activation. PSCs heterogeneity and functions are characterized through bulk, single‐cell, and spatial transcriptomes, as well as in situ sequencing. The clinical relevance of PSCs in immunotherapy is assessed using an in‐house immune‐checkpoint blockade (ICB) treatment cohort. Findings showed that stress and hypoxia signaling activated PSCs in PDAC. Three common PSCs (CPSCs) and four tumor‐associated PSCs (TPSCs) are identified, each with distinct functions. CPSCs differentiated into CCL19+ TPSCs in immune‐enriched regions, MYH11+ TPSCs in the stromal region, and PLXDC1+ TPSCs, which exhibited cancer‐associated myofibroblasts (myCAFs) phenotype linked to poor prognosis. Notably, PLXDC1+ TPSCs, located near aggressive LRRC15+ myCAFs and SPP1+ macrophages, formed a desmoplastic and immunosuppressive niche around the tumor boundary, promoting CD8 T cell exhaustion. Single‐cell transcriptomics of PDAC patients treated with ICB revealed that PLXDC1+ TPSCs correlated with poor immunotherapy efficacy. Overall, this study provides key insights into PSCs in PDAC and potential therapeutic targets. |
| format | Article |
| id | doaj-art-31b82fa7577e4025984e16ed6cc3960e |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-31b82fa7577e4025984e16ed6cc3960e2025-08-20T03:11:14ZengWileyAdvanced Science2198-38442025-05-011218n/an/a10.1002/advs.202415756PLXDC1+ Tumor‐Associated Pancreatic Stellate Cells Promote Desmoplastic and Immunosuppressive Niche in Pancreatic Ductal AdenocarcinomaYanhua Du0Yizhou Zhao1Judong Li2Jiaxin Wang3Shenglan You4Yao Zhang5Li Zhang6Jihong Yang7Hamid Alinejad‐Rokny8Shujie Cheng9Chenghao Shao10Duowu Zou11Youqiong Ye12Center for Immune‐Related Diseases at Shanghai Institute of Immunology Department of Gastroenterology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200001 ChinaCenter for Immune‐Related Diseases at Shanghai Institute of Immunology Department of Gastroenterology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200001 ChinaDepartment of Pancreatic‐biliary Surgery Changzheng Hospital Naval Medical University Shanghai 200003 ChinaCenter for Immune‐Related Diseases at Shanghai Institute of Immunology Department of Gastroenterology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200001 ChinaCenter for Immune‐Related Diseases at Shanghai Institute of Immunology Department of Gastroenterology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200001 ChinaCenter for Immune‐Related Diseases at Shanghai Institute of Immunology Department of Gastroenterology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200001 ChinaCenter for Immune‐Related Diseases at Shanghai Institute of Immunology Department of Gastroenterology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200001 ChinaDepartment of Hepatobiliary Surgery Hebei Key Laboratory of General Surgery for Digital Medicine Affiliated Hospital of Hebei University Baoding 071000 ChinaUNSW BioMedical Machine Learning Lab (BML) School of Biomedical Engineering UNSW Sydney Sydney NSW 2052 AustraliaDepartment of Hepatobiliary Surgery Hebei Key Laboratory of General Surgery for Digital Medicine Affiliated Hospital of Hebei University Baoding 071000 ChinaDepartment of Pancreatic‐biliary Surgery Changzheng Hospital Naval Medical University Shanghai 200003 ChinaCenter for Immune‐Related Diseases at Shanghai Institute of Immunology Department of Gastroenterology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200001 ChinaCenter for Immune‐Related Diseases at Shanghai Institute of Immunology Department of Gastroenterology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200001 ChinaAbstract Pancreatic stellate cells (PSCs) contribute to pancreatic ductal adenocarcinoma (PDAC) progression and therapeutic resistance, yet their detailed functions remain unclear. This study combined RNA sequencing and assay for transposase‐accessible chromatin using sequencing (ATAC‐seq) on sorted PSCs from adjacent normal and PDAC tissues to investigate their transcriptional and epigenetic activation. PSCs heterogeneity and functions are characterized through bulk, single‐cell, and spatial transcriptomes, as well as in situ sequencing. The clinical relevance of PSCs in immunotherapy is assessed using an in‐house immune‐checkpoint blockade (ICB) treatment cohort. Findings showed that stress and hypoxia signaling activated PSCs in PDAC. Three common PSCs (CPSCs) and four tumor‐associated PSCs (TPSCs) are identified, each with distinct functions. CPSCs differentiated into CCL19+ TPSCs in immune‐enriched regions, MYH11+ TPSCs in the stromal region, and PLXDC1+ TPSCs, which exhibited cancer‐associated myofibroblasts (myCAFs) phenotype linked to poor prognosis. Notably, PLXDC1+ TPSCs, located near aggressive LRRC15+ myCAFs and SPP1+ macrophages, formed a desmoplastic and immunosuppressive niche around the tumor boundary, promoting CD8 T cell exhaustion. Single‐cell transcriptomics of PDAC patients treated with ICB revealed that PLXDC1+ TPSCs correlated with poor immunotherapy efficacy. Overall, this study provides key insights into PSCs in PDAC and potential therapeutic targets.https://doi.org/10.1002/advs.202415756activation, heterogeneityimmunotherapy resistancepancreatic stellate cells (PSCs); PLXDC1+ tumor‐associated PSCssingle‐cell and spatial transcriptomes |
| spellingShingle | Yanhua Du Yizhou Zhao Judong Li Jiaxin Wang Shenglan You Yao Zhang Li Zhang Jihong Yang Hamid Alinejad‐Rokny Shujie Cheng Chenghao Shao Duowu Zou Youqiong Ye PLXDC1+ Tumor‐Associated Pancreatic Stellate Cells Promote Desmoplastic and Immunosuppressive Niche in Pancreatic Ductal Adenocarcinoma Advanced Science activation, heterogeneity immunotherapy resistance pancreatic stellate cells (PSCs); PLXDC1+ tumor‐associated PSCs single‐cell and spatial transcriptomes |
| title | PLXDC1+ Tumor‐Associated Pancreatic Stellate Cells Promote Desmoplastic and Immunosuppressive Niche in Pancreatic Ductal Adenocarcinoma |
| title_full | PLXDC1+ Tumor‐Associated Pancreatic Stellate Cells Promote Desmoplastic and Immunosuppressive Niche in Pancreatic Ductal Adenocarcinoma |
| title_fullStr | PLXDC1+ Tumor‐Associated Pancreatic Stellate Cells Promote Desmoplastic and Immunosuppressive Niche in Pancreatic Ductal Adenocarcinoma |
| title_full_unstemmed | PLXDC1+ Tumor‐Associated Pancreatic Stellate Cells Promote Desmoplastic and Immunosuppressive Niche in Pancreatic Ductal Adenocarcinoma |
| title_short | PLXDC1+ Tumor‐Associated Pancreatic Stellate Cells Promote Desmoplastic and Immunosuppressive Niche in Pancreatic Ductal Adenocarcinoma |
| title_sort | plxdc1 tumor associated pancreatic stellate cells promote desmoplastic and immunosuppressive niche in pancreatic ductal adenocarcinoma |
| topic | activation, heterogeneity immunotherapy resistance pancreatic stellate cells (PSCs); PLXDC1+ tumor‐associated PSCs single‐cell and spatial transcriptomes |
| url | https://doi.org/10.1002/advs.202415756 |
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