Apoptotic cells promote circulating tumor cell survival and metastasis
Abstract During tumor progression and especially following cytotoxic therapy, cell death of both tumor and stromal cells is widespread. Despite clinical observations that high levels of apoptotic cells correlate with poorer patient outcomes, the physiological effects of dying cells on tumor progress...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08541-7 |
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| author | Cassidy E. Hagan Valerie M. Sheehan Charles M. Rezanka Meijie A. Li Laura Martínez-Escardó Kirsteen J. Campbell Annelise G. Snyder Mark Headley Andrew Oberst |
| author_facet | Cassidy E. Hagan Valerie M. Sheehan Charles M. Rezanka Meijie A. Li Laura Martínez-Escardó Kirsteen J. Campbell Annelise G. Snyder Mark Headley Andrew Oberst |
| author_sort | Cassidy E. Hagan |
| collection | DOAJ |
| description | Abstract During tumor progression and especially following cytotoxic therapy, cell death of both tumor and stromal cells is widespread. Despite clinical observations that high levels of apoptotic cells correlate with poorer patient outcomes, the physiological effects of dying cells on tumor progression remain incompletely understood. Here, we report that circulating apoptotic cells robustly enhance tumor cell metastasis to the lungs. Using intravenous metastasis models, we observed that the presence of apoptotic cells, but not cells dying by other mechanisms, supports circulating tumor cell (CTC) survival following arrest in the lung vasculature. Apoptotic cells promote CTC survival by recruiting platelets to the forming metastatic niche. Apoptotic cells externalize the phospholipid phosphatidylserine to the outer leaflet of the plasma membrane, which we found increased the activity of the coagulation initiator Tissue Factor, thereby triggering the formation of platelet clots that protect proximal CTCs. Inhibiting the ability of apoptotic cells to induce coagulation by knocking out Tissue Factor, blocking phosphatidylserine, or administering the anticoagulant heparin abrogated the pro-metastatic effect of apoptotic cells. This work demonstrates a previously unappreciated role for apoptotic cells in facilitating metastasis by establishing CTC-supportive emboli, and suggests points of intervention that may reduce the pro-metastatic effect of apoptotic cells. |
| format | Article |
| id | doaj-art-6e6ba53e6a9d434da0e8b4ede5e28ea2 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-6e6ba53e6a9d434da0e8b4ede5e28ea22025-08-20T04:02:55ZengNature PortfolioCommunications Biology2399-36422025-07-018111410.1038/s42003-025-08541-7Apoptotic cells promote circulating tumor cell survival and metastasisCassidy E. Hagan0Valerie M. Sheehan1Charles M. Rezanka2Meijie A. Li3Laura Martínez-Escardó4Kirsteen J. Campbell5Annelise G. Snyder6Mark Headley7Andrew Oberst8Department of Immunology, University of WashingtonDepartment of Immunology, University of WashingtonDepartment of Immunology, University of WashingtonDepartment of Immunology, University of WashingtonCRUK Scotland InstituteCRUK Scotland InstituteDepartment of Immunology, University of WashingtonTranslational Science and Therapeutics Division, Fred Hutchinson Cancer Research CenterDepartment of Immunology, University of WashingtonAbstract During tumor progression and especially following cytotoxic therapy, cell death of both tumor and stromal cells is widespread. Despite clinical observations that high levels of apoptotic cells correlate with poorer patient outcomes, the physiological effects of dying cells on tumor progression remain incompletely understood. Here, we report that circulating apoptotic cells robustly enhance tumor cell metastasis to the lungs. Using intravenous metastasis models, we observed that the presence of apoptotic cells, but not cells dying by other mechanisms, supports circulating tumor cell (CTC) survival following arrest in the lung vasculature. Apoptotic cells promote CTC survival by recruiting platelets to the forming metastatic niche. Apoptotic cells externalize the phospholipid phosphatidylserine to the outer leaflet of the plasma membrane, which we found increased the activity of the coagulation initiator Tissue Factor, thereby triggering the formation of platelet clots that protect proximal CTCs. Inhibiting the ability of apoptotic cells to induce coagulation by knocking out Tissue Factor, blocking phosphatidylserine, or administering the anticoagulant heparin abrogated the pro-metastatic effect of apoptotic cells. This work demonstrates a previously unappreciated role for apoptotic cells in facilitating metastasis by establishing CTC-supportive emboli, and suggests points of intervention that may reduce the pro-metastatic effect of apoptotic cells.https://doi.org/10.1038/s42003-025-08541-7 |
| spellingShingle | Cassidy E. Hagan Valerie M. Sheehan Charles M. Rezanka Meijie A. Li Laura Martínez-Escardó Kirsteen J. Campbell Annelise G. Snyder Mark Headley Andrew Oberst Apoptotic cells promote circulating tumor cell survival and metastasis Communications Biology |
| title | Apoptotic cells promote circulating tumor cell survival and metastasis |
| title_full | Apoptotic cells promote circulating tumor cell survival and metastasis |
| title_fullStr | Apoptotic cells promote circulating tumor cell survival and metastasis |
| title_full_unstemmed | Apoptotic cells promote circulating tumor cell survival and metastasis |
| title_short | Apoptotic cells promote circulating tumor cell survival and metastasis |
| title_sort | apoptotic cells promote circulating tumor cell survival and metastasis |
| url | https://doi.org/10.1038/s42003-025-08541-7 |
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