Extracellular vesicles from the lung pro-thrombotic niche drive cancer-associated thrombosis and metastasis via integrin beta 2

Serena Lucotti¹, Yusuke Ogitani², Candia M Kenific², Jacob Geri³, Young Hun Kim⁴, Jinghua Gu⁵, Uthra Balaji⁵, Linda Bojmar⁶, Lee Shaashua², Yi Song⁷, Michele Cioffi², Pernille Lauritzen², Oveen M Joseph², Tetsuhiko Asao⁸, Paul M Grandgenett⁹, Michael A Hollingsworth⁹, Christopher Peralta¹⁰, Alexandra E Pagano¹⁰, Henrik Molina¹⁰, Harry B Lengel¹¹, Elizabeth G Dunne¹¹, Xiaohong Jing¹², Madeleine Schmitter¹², Lucia Borriello¹³, Thomas Miller², Haiying Zhang², Yevgeniy Romin⁴, Katia Manova⁴, Doru Paul¹⁴, H Lawrence Remmel¹⁵, Eileen M O'Reilly¹⁶, William R Jarnagin⁷, David Kelsen¹⁶, Sharon M Castellino¹⁷, Lisa Giulino-Roth¹⁸, David R Jones¹¹, John S Condeelis¹⁹, Virginia Pascual², James B Bussel²⁰, Nancy Boudreau², Irina Matei², David Entenberg²¹, Jacqueline F Bromberg²², Diane M Simeone²³, David Lyden²⁴

Affiliations

¹ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. Electronic address: sel4002@med.cornell.edu.
² Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
³ Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
⁴ Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁵ Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
⁶ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
⁷ Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁸ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA; Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Respiratory Medicine, Juntendo University, Tokyo, Japan.
⁹ Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁰ Proteomics Resource Center, The Rockefeller University, New York, NY, USA.
¹¹ Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹² Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA.
¹³ Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA; Fox Chase Cancer Center, Cancer Signaling and Microenvironment Program, Philadelphia, PA, USA.
¹⁴ Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
¹⁵ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA; Atossa Therapeutics, Inc., Seattle, WA, USA; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁶ Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁷ Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
¹⁸ Department of Pediatrics, Division of Hematology/Oncology, Weill Cornell Medicine, New York, NY, USA.
¹⁹ Department of Surgery, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Integrated Imaging Program for Cancer Research, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Gruss-Lipper Biophotonics Center, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Department of Cell Biology, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Cancer Dormancy Institute, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
²⁰ Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA; Department of Pediatrics, Division of Hematology/Oncology, Weill Cornell Medicine, New York, NY, USA.
²¹ Integrated Imaging Program for Cancer Research, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Gruss-Lipper Biophotonics Center, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Department of Cell Biology, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Cancer Dormancy Institute, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Department of Pathology, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
²² Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medicine, New York, NY, USA. Electronic address: bromberj@mskcc.org.
²³ Department of Surgery, UC San Diego Health, San Diego, CA, USA; Moores Cancer Center, UC San Diego Health, San Diego, CA, USA. Electronic address: dsimeone@ucsd.edu.
²⁴ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. Electronic address: dcl2001@med.cornell.edu.

PMID: 39938515
PMCID: PMC12452024 (available on 2026-03-20)
DOI: 10.1016/j.cell.2025.01.025

Extracellular vesicles from the lung pro-thrombotic niche drive cancer-associated thrombosis and metastasis via integrin beta 2

Serena Lucotti et al. Cell. 2025.

. 2025 Mar 20;188(6):1642-1661.e24.

doi: 10.1016/j.cell.2025.01.025. Epub 2025 Feb 11.

Authors

Affiliations

¹ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. Electronic address: sel4002@med.cornell.edu.
² Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
³ Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
⁴ Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁵ Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
⁶ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
⁷ Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁸ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA; Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Respiratory Medicine, Juntendo University, Tokyo, Japan.
⁹ Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁰ Proteomics Resource Center, The Rockefeller University, New York, NY, USA.
¹¹ Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹² Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA.
¹³ Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA; Fox Chase Cancer Center, Cancer Signaling and Microenvironment Program, Philadelphia, PA, USA.
¹⁴ Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
¹⁵ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA; Atossa Therapeutics, Inc., Seattle, WA, USA; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁶ Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁷ Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
¹⁸ Department of Pediatrics, Division of Hematology/Oncology, Weill Cornell Medicine, New York, NY, USA.
¹⁹ Department of Surgery, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Integrated Imaging Program for Cancer Research, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Gruss-Lipper Biophotonics Center, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Department of Cell Biology, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Cancer Dormancy Institute, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
²⁰ Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA; Department of Pediatrics, Division of Hematology/Oncology, Weill Cornell Medicine, New York, NY, USA.
²¹ Integrated Imaging Program for Cancer Research, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Gruss-Lipper Biophotonics Center, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Department of Cell Biology, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Cancer Dormancy Institute, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA; Department of Pathology, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
²² Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medicine, New York, NY, USA. Electronic address: bromberj@mskcc.org.
²³ Department of Surgery, UC San Diego Health, San Diego, CA, USA; Moores Cancer Center, UC San Diego Health, San Diego, CA, USA. Electronic address: dsimeone@ucsd.edu.
²⁴ Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. Electronic address: dcl2001@med.cornell.edu.

PMID: 39938515
PMCID: PMC12452024 (available on 2026-03-20)
DOI: 10.1016/j.cell.2025.01.025

Abstract

Cancer is a systemic disease with complications beyond the primary tumor site. Among them, thrombosis is the second leading cause of death in patients with certain cancers (e.g., pancreatic ductal adenocarcinoma [PDAC]) and advanced-stage disease. Here, we demonstrate that pro-thrombotic small extracellular vesicles (sEVs) are secreted by C-X-C motif chemokine 13 (CXCL13)-reprogrammed interstitial macrophages in the non-metastatic lung microenvironment of multiple cancers, a niche that we define as the pro-thrombotic niche (PTN). These sEVs package clustered integrin β₂ that dimerizes with integrin α_X and interacts with platelet-bound glycoprotein (GP)Ib to induce platelet aggregation. Blocking integrin β₂ decreases both sEV-induced thrombosis and lung metastasis. Importantly, sEV-β₂ levels are elevated in the plasma of PDAC patients prior to thrombotic events compared with patients with no history of thrombosis. We show that lung PTN establishment is a systemic consequence of cancer progression and identify sEV-β₂ as a prognostic biomarker of thrombosis risk as well as a target to prevent thrombosis and metastasis.

Keywords: cancer; cancer metastasis; cancer-associated thrombosis; extracellular vesicles; integrin beta 2; platelets; pro-thrombotic niche.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests Y.O. is employed by Daiichi Sankyo Co., Ltd., Tokyo, Japan. H.L.R. holds shares in Atossa Therapeutics, Inc. but declares no non-financial competing interests. H.L.R. is the lead independent director of Atossa Therapeutics, Inc. D.L. is on the scientific advisory board of Aufbau Holdings, Ltd. D.L. receives research grant support from Aufbau/Sonder Research X and Atossa Therapeutics.

References

1. Lucotti S, and Muschel RJ (2020). Platelets and Metastasis: New Implications of an Old Interplay. Front Oncol 10, 1350. 10.3389/fonc.2020.01350. - DOI - PMC - PubMed
1. Lucotti S, Cerutti C, Soyer M, Gil-Bernabe AM, Gomes AL, Allen PD, Smart S, Markelc B, Watson K, Armstrong PC, et al. (2019). Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A2. J Clin Invest 129, 1845–1862. 10.1172/JCI121985. - DOI - PMC - PubMed
1. Gasic GJ, Gasic TB, and Stewart CC (1968). Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci U S A 61, 46–52. 10.1073/pnas.61.1.46. - DOI - PMC - PubMed
1. Prandoni P, Falanga A, and Piccioli A (2005). Cancer and venous thromboembolism. Lancet Oncol 6, 401–410. 10.1016/S1470-2045(05)70207-2. - DOI - PubMed
1. Tuzovic M, Herrmann J, Iliescu C, Marmagkiolis K, Ziaeian B, and Yang EH (2018). Arterial Thrombosis in Patients with Cancer. Curr Treat Options Cardiovasc Med 20, 40. 10.1007/s11936-018-0635-x. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Extracellular vesicles from the lung pro-thrombotic niche drive cancer-associated thrombosis and metastasis via integrin beta 2

Affiliations

Extracellular vesicles from the lung pro-thrombotic niche drive cancer-associated thrombosis and metastasis via integrin beta 2

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials