Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth
Metastasis is the main cause of death from solid tumors. Therefore, identifying the mechanisms that govern metastatic growth poses a major biomedical challenge. Tumor microenvironment signals regulate the fate and survival of disseminated tumor cells (DTCs) in secondary organs. However, very little...
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Elsevier
2025-10-01
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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/S1476558625000995 |
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| author | L Recalde-Percaz I de la Guia-Lopez P Linzoain-Agos A Noguera-Castells M Rodrigo-Faus P Jauregui A Lopez-Plana P Fernández-Nogueira M Iniesta-González M Cueto-Remacha S Manzano R Alonso N Moragas C Baquero N Palao E Dalla FX Avilés-Jurado I Vilaseca X León-Vintró M Camacho G Fuster J Alcaraz J Aguirre-Ghiso P Gascón A Porras A Gutiérrez-Uzquiza N Carbó P Bragado |
| author_facet | L Recalde-Percaz I de la Guia-Lopez P Linzoain-Agos A Noguera-Castells M Rodrigo-Faus P Jauregui A Lopez-Plana P Fernández-Nogueira M Iniesta-González M Cueto-Remacha S Manzano R Alonso N Moragas C Baquero N Palao E Dalla FX Avilés-Jurado I Vilaseca X León-Vintró M Camacho G Fuster J Alcaraz J Aguirre-Ghiso P Gascón A Porras A Gutiérrez-Uzquiza N Carbó P Bragado |
| author_sort | L Recalde-Percaz |
| collection | DOAJ |
| description | Metastasis is the main cause of death from solid tumors. Therefore, identifying the mechanisms that govern metastatic growth poses a major biomedical challenge. Tumor microenvironment signals regulate the fate and survival of disseminated tumor cells (DTCs) in secondary organs. However, very little is known about the role of nervous system mediators in this process. We have previously reported that neuropilin-2 (NRP2) expression in breast cancer correlates with poor prognosis. Here, we show that NRP2 positively regulates the proliferation, invasion, and survival of breast and head and neck cancer cells in vitro. NRP2 deletion in tumor cells inhibits tumor growth in vivo and decreases the number and size of lung metastases by promoting lung DTCs quiescence. NRP2 deletion upregulates dormancy and cell cycle regulators expression and promotes DTCs reprograming into quiescence. Moreover, lung fibroblasts and macrophages induce NRP2 upregulation in DTCs through the secretion of TGFβ1. NRP2 facilitates lung DTC interaction with the extracellular matrix and promotes lung DTCs activation and metastasis. Therefore, we conclude that the TGFβ1-NRP2 axis is a new key dormancy-awakening inducer that promotes DTCs proliferation and lung metastasis development. |
| format | Article |
| id | doaj-art-ebd17949566c45699bf9d7567a4941fe |
| institution | Kabale University |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-ebd17949566c45699bf9d7567a4941fe2025-08-24T05:11:39ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-10-016810122010.1016/j.neo.2025.101220Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowthL Recalde-Percaz0I de la Guia-Lopez1P Linzoain-Agos2A Noguera-Castells3M Rodrigo-Faus4P Jauregui5A Lopez-Plana6P Fernández-Nogueira7M Iniesta-González8M Cueto-Remacha9S Manzano10R Alonso11N Moragas12C Baquero13N Palao14E Dalla15FX Avilés-Jurado16I Vilaseca17X León-Vintró18M Camacho19G Fuster20J Alcaraz21J Aguirre-Ghiso22P Gascón23A Porras24A Gutiérrez-Uzquiza25N Carbó26P Bragado27Department of Biomedicine, School of Medicine, Universitat de Barcelona, 08036 Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine (IBUB), Universitat de Barcelona, 08028 Barcelona, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, SpainDepartment of Biomedicine, School of Medicine, Universitat de Barcelona, 08036 Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine (IBUB), Universitat de Barcelona, 08028 Barcelona, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, SpainDepartment of Biomedicine, School of Medicine, Universitat de Barcelona, 08036 Barcelona, SpainDepartment of Biomedicine, School of Medicine, Universitat de Barcelona, 08036 Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine (IBUB), Universitat de Barcelona, 08028 Barcelona, SpainDepartment of Biomedicine, School of Medicine, Universitat de Barcelona, 08036 Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain; Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, Spain; Instituto de Investigación Sanitaria (IIS) Biodonostia, 20014 San Sebastián/Donosti, SpainDepartment of Biomedicine, School of Medicine, Universitat de Barcelona, 08036 Barcelona, SpainDepartment of Biomedicine, School of Medicine, Universitat de Barcelona, 08036 Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine (IBUB), Universitat de Barcelona, 08028 Barcelona, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, SpainDepartment of Cell Biology, Cancer Dormancy and Tumor Microenvironment Institute, Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USAFunctional Unit of Head and Neck Tumors. Otorhinolaryngology Head-Neck Surgery Department, Hospital Clínic, Barcelona, Spain; Translational Genomics and Target Therapies in Solid Tumors Group. Institut d´Investigacions Biomèdiques August Pi i Sunyer. IDIBAPS, Barcelona, Spain; Surgery and Medical-Surgical Specialties Department. Faculty of Medicine and Health Sciences. Universitat de Barcelona. Barcelona, SpainFunctional Unit of Head and Neck Tumors. Otorhinolaryngology Head-Neck Surgery Department, Hospital Clínic, Barcelona, Spain; Translational Genomics and Target Therapies in Solid Tumors Group. Institut d´Investigacions Biomèdiques August Pi i Sunyer. IDIBAPS, Barcelona, Spain; Surgery and Medical-Surgical Specialties Department. Faculty of Medicine and Health Sciences. Universitat de Barcelona. Barcelona, SpainOtorhinolaryngology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain; Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28001 Madrid, SpainGenomics of Complex Diseases, Research Institute Hospital Sant Pau, IIB Sant Pau, 08041 Barcelona, SpainDepartment of Biomedicine, School of Medicine, Universitat de Barcelona, 08036 Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain; Department of Biosciences, Faculty of Sciences and Technology, University of Vic, 08500 Vic, SpainUnit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain; Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), Barcelona 08028, SpainDepartment of Cell Biology, Cancer Dormancy and Tumor Microenvironment Institute, Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA; Gruss-Lipper Biophotonics Center, Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USADepartment of Biomedicine, School of Medicine, Universitat de Barcelona, 08036 Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine (IBUB), Universitat de Barcelona, 08028 Barcelona, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, SpainDepartment of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine (IBUB), Universitat de Barcelona, 08028 Barcelona, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, Spain; Corresponding author.Metastasis is the main cause of death from solid tumors. Therefore, identifying the mechanisms that govern metastatic growth poses a major biomedical challenge. Tumor microenvironment signals regulate the fate and survival of disseminated tumor cells (DTCs) in secondary organs. However, very little is known about the role of nervous system mediators in this process. We have previously reported that neuropilin-2 (NRP2) expression in breast cancer correlates with poor prognosis. Here, we show that NRP2 positively regulates the proliferation, invasion, and survival of breast and head and neck cancer cells in vitro. NRP2 deletion in tumor cells inhibits tumor growth in vivo and decreases the number and size of lung metastases by promoting lung DTCs quiescence. NRP2 deletion upregulates dormancy and cell cycle regulators expression and promotes DTCs reprograming into quiescence. Moreover, lung fibroblasts and macrophages induce NRP2 upregulation in DTCs through the secretion of TGFβ1. NRP2 facilitates lung DTC interaction with the extracellular matrix and promotes lung DTCs activation and metastasis. Therefore, we conclude that the TGFβ1-NRP2 axis is a new key dormancy-awakening inducer that promotes DTCs proliferation and lung metastasis development.http://www.sciencedirect.com/science/article/pii/S1476558625000995Neuropilinsdormancydisseminated tumor cellsTGFβmetastasisbreast cancer |
| spellingShingle | L Recalde-Percaz I de la Guia-Lopez P Linzoain-Agos A Noguera-Castells M Rodrigo-Faus P Jauregui A Lopez-Plana P Fernández-Nogueira M Iniesta-González M Cueto-Remacha S Manzano R Alonso N Moragas C Baquero N Palao E Dalla FX Avilés-Jurado I Vilaseca X León-Vintró M Camacho G Fuster J Alcaraz J Aguirre-Ghiso P Gascón A Porras A Gutiérrez-Uzquiza N Carbó P Bragado Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth Neoplasia: An International Journal for Oncology Research Neuropilins dormancy disseminated tumor cells TGFβ metastasis breast cancer |
| title | Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth |
| title_full | Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth |
| title_fullStr | Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth |
| title_full_unstemmed | Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth |
| title_short | Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth |
| title_sort | neuropilin 2 upregulation by stromal tgfβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth |
| topic | Neuropilins dormancy disseminated tumor cells TGFβ metastasis breast cancer |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000995 |
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