Pancreatic cancer cells infiltrate nerves through TGFbeta1-driven perineural epithelial-to-mesenchymal-like transdifferentiation
Neural invasion is a prognostic hallmark of pancreatic ductal adenocarcinoma (PDAC), yet the underlying mechanisms behind the disruption of perineural barriers and access of cancer cells into intrapancreatic nerves remain poorly understood. This study aimed to investigate the role of epithelial-mese...
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Elsevier
2025-02-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000053 |
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| author | Theresa Krauss Ibrahim Halil Gürcinar Ulrike Bourquain Maren Hieber Evelyn N. Krohmer Nan Wu Sergey Tokalov Rüdiger Goess Carmen Mota Reyes Dieter Saur Helmut Friess Güralp O. Ceyhan Ihsan Ekin Demir Okan Safak |
| author_facet | Theresa Krauss Ibrahim Halil Gürcinar Ulrike Bourquain Maren Hieber Evelyn N. Krohmer Nan Wu Sergey Tokalov Rüdiger Goess Carmen Mota Reyes Dieter Saur Helmut Friess Güralp O. Ceyhan Ihsan Ekin Demir Okan Safak |
| author_sort | Theresa Krauss |
| collection | DOAJ |
| description | Neural invasion is a prognostic hallmark of pancreatic ductal adenocarcinoma (PDAC), yet the underlying mechanisms behind the disruption of perineural barriers and access of cancer cells into intrapancreatic nerves remain poorly understood. This study aimed to investigate the role of epithelial-mesenchymal transformation (EMT) in perineural epithelial cells during neural invasion.Histopathological analysis of human and murine primary tumors using perineurium-specific GLUT1 antibody revealed a reduction in perineural integrity, which positively correlated with the extent of neural invasion in human PDAC cases. Human pancreatic cancer cell lines were found to secrete TGFbeta1, which induced EMT of perineural epithelial cells, characterized by the loss of epithelial markers (CK19-9) and the acquisition of mesenchymal markers (alphaSMA, N-Cadherin). Additionally, these transitioning perineural epithelial cells demonstrated increased matrix-degrading capabilities through the upregulation of matrix-metalloproteases 3 and 9 via SMAD2. In an autochthonous mouse model with elevated endogenous TGFbeta1 levels in addition to oncogenic Kras activation (Ptf1aCre/+, LSL-KrasG12D/+, LSL-R26Tgfβ/+), decreased perineural integrity could be reproduced in vivo.Collectively, these findings underscore the role played by TGFbeta1-overexpressing pancreatic cancer cells in the dismantling of perineural barriers during neural invasion. |
| format | Article |
| id | doaj-art-55d076062d6444029cb91b739485aadd |
| institution | Kabale University |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-55d076062d6444029cb91b739485aadd2025-02-03T04:16:37ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-02-0160101126Pancreatic cancer cells infiltrate nerves through TGFbeta1-driven perineural epithelial-to-mesenchymal-like transdifferentiationTheresa Krauss0Ibrahim Halil Gürcinar1Ulrike Bourquain2Maren Hieber3Evelyn N. Krohmer4Nan Wu5Sergey Tokalov6Rüdiger Goess7Carmen Mota Reyes8Dieter Saur9Helmut Friess10Güralp O. Ceyhan11Ihsan Ekin Demir12Okan Safak13Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany; German Cancer Consortium (DKTK), Munich site, Germany; SFB 1321, Modelling and Targeting Pancreatic Cancer, Munich, GermanyDepartment of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, GermanyDepartment of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany; German Cancer Consortium (DKTK), Munich site, Germany; SFB 1321, Modelling and Targeting Pancreatic Cancer, Munich, GermanyInstitute of Translational Cancer Research and Experimental Cancer Therapy, TranslaTUM, Munich, Germany; Department of Neurology and Neurophysiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Division of HPB Surgery, Acibadem Mehmet Ali Aydinlar University School of Medicine, Istanbul, TurkeyInstitute of Translational Cancer Research and Experimental Cancer Therapy, TranslaTUM, Munich, Germany; German Cancer Consortium (DKTK), Munich site, GermanyComprehensive Cancer Center München, Institute for Tumor Metabolism, TUM School of Medicine and Health, University Medical Center, Technical University of Munich, GermanyDepartment of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, GermanyDepartment of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, GermanyDepartment of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, GermanyInstitute of Translational Cancer Research and Experimental Cancer Therapy, TranslaTUM, Munich, Germany; German Cancer Consortium (DKTK), Munich site, Germany; SFB 1321, Modelling and Targeting Pancreatic Cancer, Munich, GermanyDepartment of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany; German Cancer Consortium (DKTK), Munich site, Germany; SFB 1321, Modelling and Targeting Pancreatic Cancer, Munich, GermanyDepartment of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany; Division of HPB Surgery, Acibadem Mehmet Ali Aydinlar University School of Medicine, Istanbul, Turkey; German Cancer Consortium (DKTK), Munich site, Germany; SFB 1321, Modelling and Targeting Pancreatic Cancer, Munich, GermanyDepartment of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany; Division of HPB Surgery, Acibadem Mehmet Ali Aydinlar University School of Medicine, Istanbul, Turkey; German Cancer Consortium (DKTK), Munich site, Germany; SFB 1321, Modelling and Targeting Pancreatic Cancer, Munich, Germany; Else Kröner Clinician Scientist Professor for Translational Pancreatic Surgery, Germany; Neural Influences in Cancer (NIC) Research Consortium, GermanyDepartment of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany; Corresponding author at: Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 München, Germany.Neural invasion is a prognostic hallmark of pancreatic ductal adenocarcinoma (PDAC), yet the underlying mechanisms behind the disruption of perineural barriers and access of cancer cells into intrapancreatic nerves remain poorly understood. This study aimed to investigate the role of epithelial-mesenchymal transformation (EMT) in perineural epithelial cells during neural invasion.Histopathological analysis of human and murine primary tumors using perineurium-specific GLUT1 antibody revealed a reduction in perineural integrity, which positively correlated with the extent of neural invasion in human PDAC cases. Human pancreatic cancer cell lines were found to secrete TGFbeta1, which induced EMT of perineural epithelial cells, characterized by the loss of epithelial markers (CK19-9) and the acquisition of mesenchymal markers (alphaSMA, N-Cadherin). Additionally, these transitioning perineural epithelial cells demonstrated increased matrix-degrading capabilities through the upregulation of matrix-metalloproteases 3 and 9 via SMAD2. In an autochthonous mouse model with elevated endogenous TGFbeta1 levels in addition to oncogenic Kras activation (Ptf1aCre/+, LSL-KrasG12D/+, LSL-R26Tgfβ/+), decreased perineural integrity could be reproduced in vivo.Collectively, these findings underscore the role played by TGFbeta1-overexpressing pancreatic cancer cells in the dismantling of perineural barriers during neural invasion.http://www.sciencedirect.com/science/article/pii/S1476558625000053Pancreatic cancerTGFbeta1Epithelial-to-mesenchymal-like transdifferentiationNerve infiltration |
| spellingShingle | Theresa Krauss Ibrahim Halil Gürcinar Ulrike Bourquain Maren Hieber Evelyn N. Krohmer Nan Wu Sergey Tokalov Rüdiger Goess Carmen Mota Reyes Dieter Saur Helmut Friess Güralp O. Ceyhan Ihsan Ekin Demir Okan Safak Pancreatic cancer cells infiltrate nerves through TGFbeta1-driven perineural epithelial-to-mesenchymal-like transdifferentiation Neoplasia: An International Journal for Oncology Research Pancreatic cancer TGFbeta1 Epithelial-to-mesenchymal-like transdifferentiation Nerve infiltration |
| title | Pancreatic cancer cells infiltrate nerves through TGFbeta1-driven perineural epithelial-to-mesenchymal-like transdifferentiation |
| title_full | Pancreatic cancer cells infiltrate nerves through TGFbeta1-driven perineural epithelial-to-mesenchymal-like transdifferentiation |
| title_fullStr | Pancreatic cancer cells infiltrate nerves through TGFbeta1-driven perineural epithelial-to-mesenchymal-like transdifferentiation |
| title_full_unstemmed | Pancreatic cancer cells infiltrate nerves through TGFbeta1-driven perineural epithelial-to-mesenchymal-like transdifferentiation |
| title_short | Pancreatic cancer cells infiltrate nerves through TGFbeta1-driven perineural epithelial-to-mesenchymal-like transdifferentiation |
| title_sort | pancreatic cancer cells infiltrate nerves through tgfbeta1 driven perineural epithelial to mesenchymal like transdifferentiation |
| topic | Pancreatic cancer TGFbeta1 Epithelial-to-mesenchymal-like transdifferentiation Nerve infiltration |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000053 |
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