{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T13:15:20Z","timestamp":1781183720811,"version":"3.54.1"},"reference-count":101,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000057","name":"U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM007270"],"award-info":[{"award-number":["T32GM007270"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["U01CA289564"],"award-info":[{"award-number":["U01CA289564"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1038\/s42003-025-08541-7","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T13:17:10Z","timestamp":1753795030000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Apoptotic cells promote circulating tumor cell survival and metastasis"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5350-3053","authenticated-orcid":false,"given":"Cassidy E.","family":"Hagan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie M.","family":"Sheehan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles M.","family":"Rezanka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijie A.","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Mart\u00ednez-Escard\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0201-8736","authenticated-orcid":false,"given":"Kirsteen J.","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3038-8099","authenticated-orcid":false,"given":"Annelise G.","family":"Snyder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0924-9326","authenticated-orcid":false,"given":"Mark","family":"Headley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9500-7912","authenticated-orcid":false,"given":"Andrew","family":"Oberst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,29]]},"reference":[{"key":"8541_CR1","doi-asserted-by":"publisher","first-page":"5574","DOI":"10.1002\/cam4.2474","volume":"8","author":"H Dillek\u00e5s","year":"2019","unstructured":"Dillek\u00e5s, H., Rogers, M. S. & Straume, O. Are 90% of deaths from cancer caused by metastases?. Cancer Med. 8, 5574\u20135576 (2019).","journal-title":"Cancer Med."},{"key":"8541_CR2","doi-asserted-by":"publisher","unstructured":"Fares, J., Fares, M. Y., Khachfe, H. H., Salhab, H. A. & Fares, Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct. Target. Ther. 5, https:\/\/doi.org\/10.1038\/s41392-020-0134-x (2020).","DOI":"10.1038\/s41392-020-0134-x"},{"key":"8541_CR3","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/nrc3004","volume":"11","author":"LJ Gay","year":"2011","unstructured":"Gay, L. J. & Felding-Habermann, B. Contribution of platelets to tumour metastasis. Nat. Rev. Cancer 11, 123\u2013134 (2011).","journal-title":"Nat. Rev. Cancer"},{"key":"8541_CR4","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1111\/bjh.12381","volume":"162","author":"AM Gil-Bernab\u00e9","year":"2013","unstructured":"Gil-Bernab\u00e9, A. M., Lucotti, S. & Muschel, R. J. Coagulation and metastasis: What does the experimental literature tell us?. Br. J. Haematol. 162, 433\u2013441 (2013).","journal-title":"Br. J. Haematol."},{"key":"8541_CR5","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.3389\/fonc.2020.01350","volume":"10","author":"S Lucotti","year":"2020","unstructured":"Lucotti, S. & Muschel, R. J. Platelets and metastasis: new implications of an old interplay. Front. Oncol. 10, 1350 (2020).","journal-title":"Front. Oncol."},{"key":"8541_CR6","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1007\/s10585-014-9660-7","volume":"31","author":"K Egan","year":"2014","unstructured":"Egan, K., Cooke, N. & Kenny, D. Living in shear: platelets protect cancer cells from shear induced damage. Clin. Exp. Metastasis 31, 697\u2013704 (2014).","journal-title":"Clin. Exp. Metastasis"},{"key":"8541_CR7","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1182\/blood-2004-06-2272","volume":"105","author":"JS Palumbo","year":"2005","unstructured":"Palumbo, J. S. et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 105, 178\u2013185 (2005).","journal-title":"Blood"},{"key":"8541_CR8","doi-asserted-by":"publisher","unstructured":"L\u00f3 Pez-Soto, A., Gonzalez, S., Smyth, M. J. & Galluzzi, L. Control of metastasis by NK cells. https:\/\/doi.org\/10.1016\/j.ccell.2017.06.009 (2017).","DOI":"10.1016\/j.ccell.2017.06.009"},{"key":"8541_CR9","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1158\/0008-5472.CAN-11-1872","volume":"72","author":"T Placke","year":"2012","unstructured":"Placke, T. et al. Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res. 72, 440\u2013448 (2012).","journal-title":"Cancer Res."},{"key":"8541_CR10","doi-asserted-by":"publisher","first-page":"E3053","DOI":"10.1073\/pnas.1411082111","volume":"111","author":"M Labelle","year":"2014","unstructured":"Labelle, M., Begum, S. & Hynes, R. O. Platelets guide the formation of early metastatic niches. Proc. Natl. Acad. Sci. USA 111, E3053\u2013E3061 (2014).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"8541_CR11","doi-asserted-by":"publisher","first-page":"3164","DOI":"10.1182\/blood-2011-08-376426","volume":"119","author":"AM Gil-Bernab\u00e9","year":"2012","unstructured":"Gil-Bernab\u00e9, A. M. et al. Recruitment of monocytes\/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood 119, 3164\u20133175 (2012).","journal-title":"Blood"},{"key":"8541_CR12","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.ccr.2013.05.008","volume":"24","author":"D Schumacher","year":"2013","unstructured":"Schumacher, D., Strilic, B., Sivaraj, K. K., Wettschureck, N. & Offermanns, S. Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via P2Y2 receptor. Cancer Cell 24, 130\u2013137 (2013).","journal-title":"Cancer Cell"},{"key":"8541_CR13","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1016\/j.trecan.2021.07.001","volume":"7","author":"E Schuster","year":"2021","unstructured":"Schuster, E. et al. Better together: circulating tumor cell clustering in metastatic cancer. Trends Cancer 7, 1020\u20131032 (2021).","journal-title":"Trends Cancer"},{"key":"8541_CR14","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1016\/j.cell.2014.07.013","volume":"158","author":"N Aceto","year":"2014","unstructured":"Aceto, N. et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158, 1110\u20131122 (2014).","journal-title":"Cell"},{"key":"8541_CR15","doi-asserted-by":"publisher","first-page":"E854","DOI":"10.1073\/pnas.1508541113","volume":"113","author":"KJ Cheung","year":"2016","unstructured":"Cheung, K. J. et al. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc. Natl. Acad. Sci. USA 113, E854\u2013E863 (2016).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"8541_CR16","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1126\/science.aaf6546","volume":"352","author":"KJ Cheung","year":"2016","unstructured":"Cheung, K. J. & Ewald, A. J. A collective route to metastasis: seeding by tumor cell clusters. Science 352, 167\u2013169 (2016).","journal-title":"Science"},{"key":"8541_CR17","first-page":"773","volume":"45","author":"IJ Fidler","year":"1970","unstructured":"Fidler, I. J. Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with l-5-lodo-2 \u2019-deoxyuridine. J. Natl. Cancer Inst. 45, 773\u2013782 (1970).","journal-title":"J. Natl. Cancer Inst."},{"key":"8541_CR18","doi-asserted-by":"publisher","first-page":"e6562","DOI":"10.1371\/journal.pone.0006562","volume":"4","author":"B Qian","year":"2009","unstructured":"Qian, B. et al. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS ONE 4, e6562 (2009).","journal-title":"PLoS ONE"},{"key":"8541_CR19","doi-asserted-by":"publisher","unstructured":"Grigoryeva, E. S. et al. The novel association of early apoptotic circulating tumor cells with treatment outcomes in breast cancer patients. Int. J. Mol. Sci. 23, https:\/\/doi.org\/10.3390\/ijms23169475 (2022).","DOI":"10.3390\/ijms23169475"},{"key":"8541_CR20","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-016-2406-y","volume":"16","author":"S Jansson","year":"2016","unstructured":"Jansson, S., Bendahl, P. O., Larsson, A. M., Aaltonen, K. E. & Ryd\u00e9n, L. Prognostic impact of circulating tumor cell apoptosis and clusters in serial blood samples from patients with metastatic breast cancer in a prospective observational cohort. BMC Cancer 16, 433 (2016).","journal-title":"BMC Cancer"},{"key":"8541_CR21","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/S0002-9440(10)61667-7","volume":"159","author":"G M\u00e9hes","year":"2001","unstructured":"M\u00e9hes, G., Witt, A., Kubista, E. & Ambros, P. F. Circulating breast cancer cells are frequently apoptotic. Am. J. Pathol. 159, 17\u201320 (2001).","journal-title":"Am. J. Pathol."},{"key":"8541_CR22","doi-asserted-by":"publisher","first-page":"1886","DOI":"10.1158\/1535-7163.MCT-12-1167","volume":"12","author":"G Kallergi","year":"2013","unstructured":"Kallergi, G. et al. Apoptotic circulating tumor cells in early and metastatic breast cancer patients. Mol. Cancer Ther. 12, 1886\u20131895 (2013).","journal-title":"Mol. Cancer Ther."},{"key":"8541_CR23","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1200\/JCO.2010.33.3716","volume":"30","author":"JM Hou","year":"2012","unstructured":"Hou, J. M. et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J. Clin. Oncol. 30, 525\u2013532 (2012).","journal-title":"J. Clin. Oncol."},{"key":"8541_CR24","doi-asserted-by":"crossref","unstructured":"Marusyk, A., Porter, C. C., Zaberezhnyy, V. & DeGregori, J. Irradiation selects for p53-deficient hematopoietic progenitors. PLoS Biol. 8, e1000324 (2010).","DOI":"10.1371\/journal.pbio.1000324"},{"key":"8541_CR25","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1038\/nm.2385","volume":"17","author":"Q Huang","year":"2011","unstructured":"Huang, Q. et al. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med. 17, 860\u2013866 (2011).","journal-title":"Nat. Med."},{"key":"8541_CR26","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/j.cub.2014.12.059","volume":"25","author":"CA Ford","year":"2015","unstructured":"Ford, C. A. et al. Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma. Curr. Biol. 25, 577\u2013588 (2015).","journal-title":"Curr. Biol."},{"key":"8541_CR27","doi-asserted-by":"publisher","first-page":"4737","DOI":"10.1172\/JCI76375","volume":"124","author":"JC Stanford","year":"2014","unstructured":"Stanford, J. C. et al. Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution. J. Clin. Investig. 124, 4737\u20134752 (2014).","journal-title":"J. Clin. Investig."},{"key":"8541_CR28","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1146\/annurev-immunol-042617-053010","volume":"36","author":"S Nagata","year":"2018","unstructured":"Nagata, S. Apoptosis and clearance of apoptotic cells. Annu. Rev. Immunol. 36, 489\u2013517 (2018).","journal-title":"Annu. Rev. Immunol."},{"key":"8541_CR29","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1111\/imr.12587","volume":"280","author":"S Kumar","year":"2017","unstructured":"Kumar, S., Calianese, D. & Birge, R. B. Efferocytosis of dying cells differentially modulate immunological outcomes in tumor microenvironment. Immunol. Rev. 280, 149\u2013164 (2017).","journal-title":"Immunol. Rev."},{"key":"8541_CR30","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1038\/cdd.2016.11","volume":"23","author":"RB Birge","year":"2016","unstructured":"Birge, R. B. et al. Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death Differ. 23, 962\u2013978 (2016).","journal-title":"Cell Death Differ."},{"key":"8541_CR31","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1007\/s10585-005-2908-5","volume":"22","author":"AD Borowsky","year":"2005","unstructured":"Borowsky, A. D. et al. Syngeneic mouse mammary carcinoma cell lines: two closely related cell lines with divergent metastatic behavior. Clin. Exp. Metastasis 22, 47\u201359 (2005).","journal-title":"Clin. Exp. Metastasis"},{"key":"8541_CR32","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1126\/science.aad0395","volume":"350","author":"N Yatim","year":"2015","unstructured":"Yatim, N. et al. RIPK1 and NF-\u03baB signaling in dying cells determines cross-priming of CD8+ T cells. Science 350, 328\u2013334 (2015).","journal-title":"Science"},{"key":"8541_CR33","doi-asserted-by":"publisher","first-page":"2004","DOI":"10.1126\/sciimmunol.aaw2004","volume":"4","author":"AG Snyder","year":"2019","unstructured":"Snyder, A. G. et al. Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity. Sci. Immunol. 4, 2004 (2019).","journal-title":"Sci. Immunol."},{"key":"8541_CR34","doi-asserted-by":"publisher","first-page":"2275","DOI":"10.1016\/j.celrep.2019.07.077","volume":"28","author":"SL Orozco","year":"2019","unstructured":"Orozco, S. L. et al. RIPK3 activation leads to cytokine synthesis that continues after loss of cell membrane integrity. Cell Rep. 28, 2275\u20132287.e5 (2019).","journal-title":"Cell Rep."},{"key":"8541_CR35","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1038\/cdd.2014.76","volume":"21","author":"S Orozco","year":"2014","unstructured":"Orozco, S. et al. RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis. Cell Death Differ. 21, 1511\u20131521 (2014).","journal-title":"Cell Death Differ."},{"key":"8541_CR36","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1093\/intimm\/12.11.1539","volume":"12","author":"S Basu","year":"2000","unstructured":"Basu, S., Binder, R. J., Suto, R., Anderson, K. M. & Srivastava, P. K. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-\u03baB pathway. Int. Immunol. 12, 1539\u20131546 (2000).","journal-title":"Int. Immunol."},{"key":"8541_CR37","doi-asserted-by":"publisher","first-page":"21677","DOI":"10.1073\/pnas.1016234107","volume":"107","author":"DG Duda","year":"2010","unstructured":"Duda, D. G. et al. Malignant cells facilitate lung metastasis by bringing their own soil. Proc. Natl. Acad. Sci. USA 107, 21677\u201321682 (2010).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"8541_CR38","doi-asserted-by":"publisher","first-page":"4681","DOI":"10.1158\/0008-5472.CAN-15-1633","volume":"75","author":"Z Ao","year":"2015","unstructured":"Ao, Z. et al. Identification of cancer-associated fibroblasts in circulating blood from patients with metastatic breast cancer. Cancer Res. 75, 4681\u20134687 (2015).","journal-title":"Cancer Res."},{"key":"8541_CR39","doi-asserted-by":"crossref","unstructured":"Rogers, C. et al. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic\/pyroptotic cell death. Nat. Commun. 8, 14128 (2017).","DOI":"10.1038\/ncomms14128"},{"key":"8541_CR40","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/nature16985","volume":"531","author":"MB Headley","year":"2016","unstructured":"Headley, M. B. et al. Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature 531, 513\u2013517 (2016).","journal-title":"Nature"},{"key":"8541_CR41","doi-asserted-by":"publisher","first-page":"4887","DOI":"10.1016\/j.cell.2022.11.029","volume":"185","author":"S Morioka","year":"2022","unstructured":"Morioka, S. et al. Chimeric efferocytic receptors improve apoptotic cell clearance and alleviate inflammation. Cell 185, 4887\u20134903 (2022).","journal-title":"Cell"},{"key":"8541_CR42","doi-asserted-by":"crossref","unstructured":"Ichise, H. et al. Functional visualization of NK cell-mediated killing of metastatic single tumor cells. eLife. 11, e76269 (2022).","DOI":"10.7554\/eLife.76269"},{"key":"8541_CR43","doi-asserted-by":"crossref","unstructured":"Chan, I. S. & Ewald, A. J. The changing role of natural killer cells in cancer metastasis. J. Clin. Investig. 132, e143762 (2022).","DOI":"10.1172\/JCI143762"},{"key":"8541_CR44","doi-asserted-by":"publisher","first-page":"2731","DOI":"10.1073\/pnas.050588297","volume":"97","author":"S Kim","year":"2000","unstructured":"Kim, S., Iizuka, K., Aguila, H. L., Weissman, I. L. & Yokoyama, W. M. In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc. Natl. Acad. Sci. USA 97, 2731\u20132736 (2000).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"8541_CR45","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1002\/ar.20747","volume":"292","author":"J Knust","year":"2009","unstructured":"Knust, J., Ochs, M., Gundersen, H. J. G. & Nyengaard, J. R. Stereological estimates of alveolar number and size and capillary length and surface area in mice lungs. Anat. Rec. 292, 113\u2013122 (2009).","journal-title":"Anat. Rec."},{"key":"8541_CR46","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/s41586-019-0915-y","volume":"566","author":"BM Szczerba","year":"2019","unstructured":"Szczerba, B. M. et al. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature 566, 553\u2013557 (2019).","journal-title":"Nature"},{"key":"8541_CR47","doi-asserted-by":"publisher","unstructured":"Brake, M. A. et al. Assessing blood clotting and coagulation factors in mice. Curr. Protoc. Mouse Biol. https:\/\/doi.org\/10.1002\/cpmo.61 (2019).","DOI":"10.1002\/cpmo.61"},{"key":"8541_CR48","doi-asserted-by":"publisher","first-page":"1687","DOI":"10.1161\/ATVBAHA.107.141911","volume":"27","author":"N Mackman","year":"2007","unstructured":"Mackman, N., Tilley, R. E. & Key, N. S. Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler. Thromb. Vasc. Biol. 27, 1687\u20131693 (2007).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"8541_CR49","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1161\/ATVBAHA.117.309846","volume":"38","author":"SP Grover","year":"2018","unstructured":"Grover, S. P. & Mackman, N. Tissue factor: an essential mediator of hemostasis and trigger of thrombosis. Arterioscler. Thromb. Vasc. Biol. 38, 709\u2013725 (2018).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"8541_CR50","doi-asserted-by":"publisher","first-page":"4834","DOI":"10.1200\/JCO.2009.22.6324","volume":"27","author":"RS Kasthuri","year":"2009","unstructured":"Kasthuri, R. S., Taubman, M. B. & Mackman, N. Role of tissue factor in cancer. J. Clin. Oncol. 27, 4834\u20134838 (2009).","journal-title":"J. Clin. Oncol."},{"key":"8541_CR51","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1182\/blood-2007-01-065995","volume":"110","author":"JS Palumbo","year":"2007","unstructured":"Palumbo, J. S. et al. Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and -independent mechanisms. Blood 110, 133\u2013141 (2007).","journal-title":"Blood"},{"key":"8541_CR52","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.2741\/e477","volume":"4","author":"LVM Rao","year":"2012","unstructured":"Rao, L. V. M., Kothari, H. & Pendurthi, U. R. Tissue factor: mechanisms of decryption. Front. Biosci. 4, 1513\u20131527 (2012).","journal-title":"Front. Biosci."},{"key":"8541_CR53","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1111\/j.1538-7836.2009.03448.x","volume":"7","author":"J-G Wang","year":"2009","unstructured":"Wang, J.-G., Manly, D., Kirchhofer, D., Pawlinski, R. & Mackman, N. Levels of microparticle tissue factor activity correlate with coagulation activation in endotoxemic mice. J. Thromb. Haemost. 7, 1092\u20131098 (2009).","journal-title":"J. Thromb. Haemost."},{"key":"8541_CR54","doi-asserted-by":"publisher","unstructured":"Schmaier, A. A. et al. TMEM16E regulates endothelial cell procoagulant activity and thrombosis. J. Clin. Investig. 133, https:\/\/doi.org\/10.1172\/JCI163808 (2023).","DOI":"10.1172\/JCI163808"},{"key":"8541_CR55","doi-asserted-by":"publisher","first-page":"6556","DOI":"10.1074\/jbc.M607973200","volume":"282","author":"AW Shaw","year":"2007","unstructured":"Shaw, A. W., Pureza, V. S., Sligar, S. G. & Morrissey, J. H. The local phospholipid environment modulates the activation of blood clotting. J. Biol. Chem. 282, 6556\u20136563 (2007).","journal-title":"J. Biol. Chem."},{"key":"8541_CR56","doi-asserted-by":"publisher","first-page":"S54","DOI":"10.1016\/j.thromres.2014.03.022","volume":"133","author":"HMH Spronk","year":"2014","unstructured":"Spronk, H. M. H., Ten Cate, H. & Van Der Meijden, P. E. J. Differential roles of tissue factor and phosphatidylserine in activation of coagulation. Thromb. Res. 133, S54\u2013S56 (2014).","journal-title":"Thromb. Res."},{"key":"8541_CR57","doi-asserted-by":"publisher","first-page":"6995","DOI":"10.1073\/pnas.87.18.6995","volume":"87","author":"R Bach","year":"1990","unstructured":"Bach, R. & Rifkin, D. B. Expression of tissue factor procoagulant activity: regulation by cytosolic calcium. Proc. Natl. Acad. Sci. USA 87, 6995\u20136999 (1990).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"8541_CR58","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1126\/science.1252809","volume":"344","author":"K Segawa","year":"2014","unstructured":"Segawa, K. et al. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344, 1164\u20131168 (2014).","journal-title":"Science"},{"key":"8541_CR59","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1038\/cdd.2016.7","volume":"23","author":"S Nagata","year":"2016","unstructured":"Nagata, S., Suzuki, J., Segawa, K. & Fujii, T. Exposure of phosphatidylserine on the cell surface. Cell Death Differ. 23, 952\u2013961 (2016).","journal-title":"Cell Death Differ."},{"key":"8541_CR60","doi-asserted-by":"publisher","first-page":"241","DOI":"10.3389\/fimmu.2018.00241","volume":"9","author":"DS Ucker","year":"2018","unstructured":"Ucker, D. S. & Levine, J. S. Exploitation of apoptotic regulation in cancer. Front Immunol. 9, 241 (2018).","journal-title":"Front Immunol."},{"key":"8541_CR61","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1038\/nrc.2016.58","volume":"16","author":"G Ichim","year":"2016","unstructured":"Ichim, G. & Tait, S. W. G. A fate worse than death: apoptosis as an oncogenic process. Nat. Rev. Cancer 16, 539\u2013548 (2016).","journal-title":"Nat. Rev. Cancer"},{"key":"8541_CR62","doi-asserted-by":"crossref","unstructured":"Castillo Ferrer, C., Berthenet, K. & Ichim, G. Apoptosis\u2014fueling the oncogenic fire. FEBS J. 288, 4445\u20134463 (2021).","DOI":"10.1111\/febs.15624"},{"key":"8541_CR63","doi-asserted-by":"crossref","unstructured":"Unruh, D. & Horbinski, C. Beyond thrombosis: the impact of tissue factor signaling in cancer. J. Hematol. Oncol. 13, 93 (2020).","DOI":"10.1186\/s13045-020-00932-z"},{"key":"8541_CR64","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.18632\/oncotarget.27510","volume":"11","author":"N Ortiz-Otero","year":"2020","unstructured":"Ortiz-Otero, N. et al. Cancer associated fibroblasts confer shear resistance to circulating tumor cells during prostate cancer metastatic progression. Oncotarget 11, 1037\u20131050 (2020).","journal-title":"Oncotarget"},{"key":"8541_CR65","doi-asserted-by":"crossref","unstructured":"Lu, T., Oomens, L., Terstappen, L. W. M. M. & Prakash, J. In vivo detection of circulating cancer-associated fibroblasts in breast tumor mouse xenograft: impact of tumor stroma and chemotherapy. Cancers 15, 1127 (2023).","DOI":"10.3390\/cancers15041127"},{"key":"8541_CR66","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1080\/10245332.2001.11746565","volume":"6","author":"J Wang","year":"2001","unstructured":"Wang, J. & Kwaan, H. C. The pathogenetic role of apoptosis in hypercoagulable states. Hematology 6, 143\u2013152 (2001).","journal-title":"Hematology"},{"key":"8541_CR67","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1016\/j.immuni.2019.11.005","volume":"51","author":"X Yang","year":"2019","unstructured":"Yang, X. et al. Bacterial endotoxin activates the coagulation cascade through gasdermin D-dependent phosphatidylserine exposure. Immunity 51, 983\u2013996.e6 (2019).","journal-title":"Immunity"},{"key":"8541_CR68","doi-asserted-by":"publisher","first-page":"4545","DOI":"10.1182\/blood-2003-03-0713","volume":"103","author":"O Aras","year":"2004","unstructured":"Aras, O. et al. Induction of microparticle- and cell-associated intravascular tissue factor in human endotoxemia. Blood 103, 4545\u20134553 (2004).","journal-title":"Blood"},{"key":"8541_CR69","doi-asserted-by":"publisher","first-page":"2429","DOI":"10.1182\/blood.V89.7.2429","volume":"89","author":"T Bombeli","year":"1997","unstructured":"Bombeli, T., Karsan, A., Tait, J. F. & Harlan, J. M. Apoptotic vascular endothelial cells become procoagulant. Blood 89, 2429\u20132442 (1997).","journal-title":"Blood"},{"key":"8541_CR70","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.bbagen.2016.11.020","volume":"1861","author":"MR Muhsin-Sharafaldine","year":"2017","unstructured":"Muhsin-Sharafaldine, M. R. et al. Mechanistic insight into the procoagulant activity of tumor-derived apoptotic vesicles. Biochim. Biophys. Acta Gen. Subj. 1861, 286\u2013295 (2017).","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"8541_CR71","doi-asserted-by":"publisher","first-page":"56279","DOI":"10.18632\/oncotarget.10783","volume":"7","author":"MR Muhsin-Sharafaldine","year":"2016","unstructured":"Muhsin-Sharafaldine, M. R. et al. Procoagulant and immunogenic properties of melanoma exosomes, microvesicles and apoptotic vesicles. Oncotarget 7, 56279\u201356294 (2016).","journal-title":"Oncotarget"},{"key":"8541_CR72","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1111\/imcb.12162","volume":"96","author":"MR Muhsin-Sharafaldine","year":"2018","unstructured":"Muhsin-Sharafaldine, M. R. & McLellan, A. D. Apoptotic vesicles: deathly players in cancer-associated coagulation. Immunol. Cell Biol. 96, 723\u2013732 (2018).","journal-title":"Immunol. Cell Biol."},{"key":"8541_CR73","doi-asserted-by":"publisher","first-page":"6445","DOI":"10.7150\/thno.53637","volume":"11","author":"C Zhang","year":"2021","unstructured":"Zhang, C. et al. Phosphatidylserine-exposing tumor-derived microparticles exacerbate coagulation and cancer cell transendothelial migration in triple-negative breast cancer. Theranostics 11, 6445\u20136460 (2021).","journal-title":"Theranostics"},{"key":"8541_CR74","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1161\/ATVBAHA.120.314378","volume":"41","author":"SP Grover","year":"2021","unstructured":"Grover, S. P., Hisada, Y. M., Kasthuri, R. S., Reeves, B. N. & MacKman, N. Cancer therapy-associated thrombosis. Arterioscler. Thromb. Vasc. Biol. 41, 1291\u20131305 (2021).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"8541_CR75","doi-asserted-by":"crossref","unstructured":"Khalil, J. et al. Venous thromboembolism in cancer patients: an underestimated major health problem. World J. Surg. Oncol. 13, 204 (2015).","DOI":"10.1186\/s12957-015-0592-8"},{"key":"8541_CR76","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1111\/j.1538-7836.2007.02374.x","volume":"5","author":"AA Khorana","year":"2007","unstructured":"Khorana, A. A., Francis, C. W., Culakova, E., Kuderer, N. M. & Lyman, G. H. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J. Thromb. Haemost. 5, 632\u2013634 (2007).","journal-title":"J. Thromb. Haemost."},{"key":"8541_CR77","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.canlet.2009.03.041","volume":"283","author":"LG Lima","year":"2009","unstructured":"Lima, L. G., Chammas, R., Monteiro, R. Q., Moreira, M. E. C. & Barcinski, M. A. Tumor-derived microvesicles modulate the establishment of metastatic melanoma in a phosphatidylserine-dependent manner. Cancer Lett. 283, 168\u2013175 (2009).","journal-title":"Cancer Lett."},{"key":"8541_CR78","doi-asserted-by":"crossref","unstructured":"Jing, H. et al. Microparticle phosphatidylserine mediates coagulation: involvement in tumor progression and metastasis. Cancers 15, 1957 (2023).","DOI":"10.3390\/cancers15071957"},{"key":"8541_CR79","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.semcancer.2017.08.012","volume":"52","author":"B Sharma","year":"2018","unstructured":"Sharma, B. & Kanwar, S. S. Phosphatidylserine: a cancer cell targeting biomarker. Semin. Cancer Biol. 52, 17\u201325 (2018).","journal-title":"Semin. Cancer Biol."},{"key":"8541_CR80","doi-asserted-by":"publisher","first-page":"108620","DOI":"10.1016\/j.celrep.2020.108620","volume":"34","author":"S Budhu","year":"2021","unstructured":"Budhu, S. et al. Targeting phosphatidylserine enhances the anti-tumor response to tumor-directed radiation therapy in a preclinical model of melanoma. Cell Rep. 34, 108620 (2021).","journal-title":"Cell Rep."},{"key":"8541_CR81","doi-asserted-by":"publisher","first-page":"111582","DOI":"10.1016\/j.celrep.2022.111582","volume":"41","author":"W Wang","year":"2022","unstructured":"Wang, W. et al. Mobilizing phospholipids on tumor plasma membrane implicates phosphatidylserine externalization blockade for cancer immunotherapy. Cell Rep. 41, 111582 (2022).","journal-title":"Cell Rep."},{"key":"8541_CR82","first-page":"3062","volume":"51","author":"T Utsugi","year":"1991","unstructured":"Utsugi, T., Schroit, A. J., Connor, J., Bucana, C. D. & Fidler, I. J. Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes. Cancer Res. 51, 3062\u20133066 (1991).","journal-title":"Cancer Res."},{"key":"8541_CR83","doi-asserted-by":"publisher","first-page":"2638","DOI":"10.1016\/j.bbamem.2011.07.026","volume":"1808","author":"S Riedl","year":"2011","unstructured":"Riedl, S. et al. In search of a novel target\u2014phosphatidylserine exposed by non-apoptotic tumor cells and metastases of malignancies with poor treatment efficacy. Biochim. Biophys. Acta 1808, 2638\u20132645 (2011).","journal-title":"Biochim. Biophys. Acta"},{"key":"8541_CR84","doi-asserted-by":"publisher","unstructured":"Kaynak, A. et al. Phosphatidylserine: the unique dual-role biomarker for cancer imaging and therapy. Cancers 14, https:\/\/doi.org\/10.3390\/cancers14102536 (2022).","DOI":"10.3390\/cancers14102536"},{"key":"8541_CR85","doi-asserted-by":"publisher","first-page":"15447","DOI":"10.1016\/S0021-9258(19)49554-9","volume":"267","author":"DT Le","year":"1992","unstructured":"Le, D. T., Rapaport, S. I. & Rao, L. V. M. Relations between factor VIla binding and expression of factor VIIa\/tissue factor catalytic activity on cell surfaces. J. Biol. Chem. 267, 15447\u201315454 (1992).","journal-title":"J. Biol. Chem."},{"key":"8541_CR86","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1182\/blood.V76.2.361.361","volume":"76","author":"SD Carson","year":"1990","unstructured":"Carson, S. D. & Johnson, D. R. Consecutive enzyme cascades: Complement activation at the cell surface triggers increased tissue factor activity. Blood 76, 361\u2013367 (1990).","journal-title":"Blood"},{"key":"8541_CR87","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/0049-3848(86)90228-8","volume":"41","author":"SD Carson","year":"1986","unstructured":"Carson, S. D. & Archer, P. G. Tissue factor activity in HeLa cells measured with a continuous chromogenic assay and ELISA reader. Thromb. Res. 41, 185\u2013195 (1986).","journal-title":"Thromb. Res."},{"key":"8541_CR88","doi-asserted-by":"publisher","first-page":"8","DOI":"10.4161\/onci.25669","volume":"2","author":"M Tard\u00e1guila","year":"2013","unstructured":"Tard\u00e1guila, M. & Ma\u00f1es, S. CX3CL1 at the crossroad of EGF signals relevance for the progression of ERBB2+ breast carcinoma. Oncoimmunology 2, 8\u201310 (2013).","journal-title":"Oncoimmunology"},{"key":"8541_CR89","doi-asserted-by":"publisher","first-page":"7907","DOI":"10.3892\/mmr.2015.4438","volume":"12","author":"J Tang","year":"2015","unstructured":"Tang, J. et al. Upregulation of fractalkine contributes to the proliferative response of prostate cancer cells to hypoxia via promoting the G1\/S phase transition. Mol. Med. Rep. 12, 7907\u20137914 (2015).","journal-title":"Mol. Med. Rep."},{"key":"8541_CR90","doi-asserted-by":"publisher","first-page":"1615","DOI":"10.3892\/ol.2013.1223","volume":"5","author":"P Mao","year":"2013","unstructured":"Mao, P., Smith, L., Xie, W. & Wang, M. Dying endothelial cells stimulate proliferation of malignant glioma cells via a caspase 3-mediated pathway. Oncol. Lett. 5, 1615\u20131620 (2013).","journal-title":"Oncol. Lett."},{"key":"8541_CR91","doi-asserted-by":"publisher","first-page":"317","DOI":"10.3109\/08916934.2012.754433","volume":"46","author":"R Chaurio","year":"2013","unstructured":"Chaurio, R. et al. UVB-irradiated apoptotic cells induce accelerated growth of co-implanted viable tumor cells in immune competent mice. Autoimmunity 46, 317\u2013322 (2013).","journal-title":"Autoimmunity"},{"key":"8541_CR92","doi-asserted-by":"publisher","unstructured":"Medina, C. B. et al. Metabolites released from apoptotic cells act as tissue messengers. Nature https:\/\/doi.org\/10.1038\/s41586-020-2121-3 (2020).","DOI":"10.1038\/s41586-020-2121-3"},{"key":"8541_CR93","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1038\/ncb3194","volume":"17","author":"PW Furlow","year":"2015","unstructured":"Furlow, P. W. et al. Mechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival. Nat. Cell Biol. 17, 943\u2013952 (2015).","journal-title":"Nat. Cell Biol."},{"key":"8541_CR94","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1038\/ncb3596","volume":"19","author":"E Giampazolias","year":"2017","unstructured":"Giampazolias, E. et al. Mitochondrial permeabilization engages NF-\u03baB-dependent anti-tumour activity under caspase deficiency. Nat. Cell Biol. 19, 1116\u20131129 (2017).","journal-title":"Nat. Cell Biol."},{"key":"8541_CR95","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1093\/jnci\/91.1.22","volume":"91","author":"M Hejna","year":"1999","unstructured":"Hejna, M., Raderer, M. & Zielinski, C. C. Inhibition of metastases by anticoagulants. J. Natl. Cancer Inst. 91, 22\u201336 (1999).","journal-title":"J. Natl. Cancer Inst."},{"key":"8541_CR96","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.thromres.2019.12.022","volume":"187","author":"S Najidh","year":"2020","unstructured":"Najidh, S., Versteeg, H. H. & Buijs, J. T. A systematic review on the effects of direct oral anticoagulants on cancer growth and metastasis in animal models. Thromb. Res. 187, 18\u201327 (2020).","journal-title":"Thromb. Res."},{"key":"8541_CR97","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.1016\/j.jacc.2019.01.017","volume":"73","author":"RC Mosarla","year":"2019","unstructured":"Mosarla, R. C. et al. Anticoagulation strategies in patients with cancer: JACC review topic of the week. J. Am. Coll. Cardiol. 73, 1336\u20131349 (2019).","journal-title":"J. Am. Coll. Cardiol."},{"key":"8541_CR98","doi-asserted-by":"crossref","unstructured":"G\u00f3rnicki, T., Bu\u0142dy\u015b, K., Zieli\u0144ska, D. & Chabowski, M. Direct-acting oral anticoagulant therapy in cancer patients\u2014a review. Cancers 15, 2697 (2023).","DOI":"10.3390\/cancers15102697"},{"key":"8541_CR99","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/978-1-4939-9167-9_7","volume":"1960","author":"YS Tan","year":"2019","unstructured":"Tan, Y. S. & Lei, Y. L. Generation and culture of mouse embryonic fibroblasts. Methods Mol. Biol. 1960, 85\u201391 (2019).","journal-title":"Methods Mol. Biol."},{"key":"8541_CR100","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1038\/ni.3201","volume":"16","author":"R Barreira Da Silva","year":"2015","unstructured":"Barreira Da Silva, R. et al. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat. Immunol. 16, 850\u2013858 (2015).","journal-title":"Nat. Immunol."},{"key":"8541_CR101","doi-asserted-by":"publisher","unstructured":"Hagan, C. Supporting data values for \u201cApoptotic cells promote circulating tumor cell survival and metastasis\u201d. figshare https:\/\/doi.org\/10.6084\/m9.figshare.25872388.v2 (2025).","DOI":"10.6084\/m9.figshare.25872388.v2"}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-025-08541-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-025-08541-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-025-08541-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T10:30:42Z","timestamp":1757327442000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-025-08541-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,29]]},"references-count":101,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["8541"],"URL":"https:\/\/doi.org\/10.1038\/s42003-025-08541-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.05.21.595217","asserted-by":"object"}]},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,29]]},"assertion":[{"value":"23 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1121"}}