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

Serena Lucotti; Yusuke Ogitani; Candia M. Kenific; Jacob Geri; Young Hun Kim; Jinghua Gu; Uthra Balaji; Linda Bojmar; Lee Shaashua; Yi Song; Michele Cioffi; Pernille Lauritzen; Oveen M. Joseph; Tetsuhiko Asao; Paul M. Grandgenett; Michael A. Hollingsworth; Christopher Peralta; Alexandra E. Pagano; Henrik Molina; Harry B. Lengel; Elizabeth G. Dunne; Xiaohong Jing; Madeleine Schmitter; Lucia Borriello; Thomas Miller; Haiying Zhang; Yevgeniy Romin; Katia Manova; Doru Paul; H. Lawrence Remmel; Eileen M. O'Reilly; William R. Jarnagin; David Kelsen; Sharon M. Castellino; Lisa Giulino-Roth; David R. Jones; John S. Condeelis; Virginia Pascual; James B. Bussel; Nancy Boudreau; Irina Matei; David Entenberg; Jacqueline F. Bromberg; Diane M. Simeone; David Lyden

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^*, Yusuke Ogitani, Candia M. Kenific, Jacob Geri, Young Hun Kim, Jinghua Gu, Uthra Balaji, Linda Bojmar, Lee Shaashua, Yi Song, Michele Cioffi, Pernille Lauritzen, Oveen M. Joseph, Tetsuhiko Asao, Paul M. Grandgenett, Michael A. Hollingsworth, Christopher Peralta, Alexandra E. Pagano, Henrik Molina, Harry B. LengelElizabeth G. Dunne, Xiaohong Jing, Madeleine Schmitter, Lucia Borriello, Thomas Miller, Haiying Zhang, Yevgeniy Romin, Katia Manova, Doru Paul, H. Lawrence Remmel, Eileen M. O'Reilly, William R. Jarnagin, David Kelsen, Sharon M. Castellino, Lisa Giulino-Roth, David R. Jones, John S. Condeelis, Virginia Pascual, James B. Bussel, Nancy Boudreau, Irina Matei, David Entenberg, Jacqueline F. Bromberg^*, Diane M. Simeone^*, David Lyden^*

^*Corresponding author for this work

Department of Pathology

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1642-1661.e24
Journal	Cell
Volume	188
Issue number	6
Early online date	11 Feb 2025
DOIs	https://doi.org/10.1016/j.cell.2025.01.025
Publication status	Published - 20 Mar 2025

Keywords

cancer
cancer metastasis
cancer-associated thrombosis
extracellular vesicles
integrin beta 2
platelets
pro-thrombotic niche

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10.1016/j.cell.2025.01.025

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Lucotti, S., Ogitani, Y., Kenific, C. M., Geri, J., Kim, Y. H., Gu, J., Balaji, U., Bojmar, L., Shaashua, L., Song, Y., Cioffi, M., Lauritzen, P., Joseph, O. M., Asao, T., Grandgenett, P. M., Hollingsworth, M. A., Peralta, C., Pagano, A. E., Molina, H., ... Lyden, D. (2025). Extracellular vesicles from the lung pro-thrombotic niche drive cancer-associated thrombosis and metastasis via integrin beta 2. Cell, 188(6), 1642-1661.e24. https://doi.org/10.1016/j.cell.2025.01.025

@article{f69d28803e544013a5168dc6fc8255ec,

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

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 αX 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",

author = "Serena Lucotti and Yusuke Ogitani and Kenific, {Candia M.} and Jacob Geri and Kim, {Young Hun} and Jinghua Gu and Uthra Balaji and Linda Bojmar and Lee Shaashua and Yi Song and Michele Cioffi and Pernille Lauritzen and Joseph, {Oveen M.} and Tetsuhiko Asao and Grandgenett, {Paul M.} and Hollingsworth, {Michael A.} and Christopher Peralta and Pagano, {Alexandra E.} and Henrik Molina and Lengel, {Harry B.} and Dunne, {Elizabeth G.} and Xiaohong Jing and Madeleine Schmitter and Lucia Borriello and Thomas Miller and Haiying Zhang and Yevgeniy Romin and Katia Manova and Doru Paul and Remmel, {H. Lawrence} and O'Reilly, {Eileen M.} and Jarnagin, {William R.} and David Kelsen and Castellino, {Sharon M.} and Lisa Giulino-Roth and Jones, {David R.} and Condeelis, {John S.} and Virginia Pascual and Bussel, {James B.} and Nancy Boudreau and Irina Matei and David Entenberg and Bromberg, {Jacqueline F.} and Simeone, {Diane M.} and David Lyden",

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Inc.",

year = "2025",

month = mar,

day = "20",

doi = "10.1016/j.cell.2025.01.025",

language = "English",

volume = "188",

pages = "1642--1661.e24",

number = "6",

}

Lucotti, S, Ogitani, Y, Kenific, CM, Geri, J, Kim, YH, Gu, J, Balaji, U, Bojmar, L, Shaashua, L, Song, Y, Cioffi, M, Lauritzen, P, Joseph, OM, Asao, T, Grandgenett, PM, Hollingsworth, MA, Peralta, C, Pagano, AE, Molina, H, Lengel, HB, Dunne, EG, Jing, X, Schmitter, M, Borriello, L, Miller, T, Zhang, H, Romin, Y, Manova, K, Paul, D, Remmel, HL, O'Reilly, EM, Jarnagin, WR, Kelsen, D, Castellino, SM, Giulino-Roth, L, Jones, DR, Condeelis, JS, Pascual, V, Bussel, JB, Boudreau, N, Matei, I, Entenberg, D, Bromberg, JF, Simeone, DM & Lyden, D 2025, 'Extracellular vesicles from the lung pro-thrombotic niche drive cancer-associated thrombosis and metastasis via integrin beta 2', Cell, vol. 188, no. 6, pp. 1642-1661.e24. https://doi.org/10.1016/j.cell.2025.01.025

TY - JOUR

T1 - Extracellular vesicles from the lung pro-thrombotic niche drive cancer-associated thrombosis and metastasis via integrin beta 2

AU - Lucotti, Serena

AU - Ogitani, Yusuke

AU - Kenific, Candia M.

AU - Geri, Jacob

AU - Kim, Young Hun

AU - Gu, Jinghua

AU - Balaji, Uthra

AU - Bojmar, Linda

AU - Shaashua, Lee

AU - Song, Yi

AU - Cioffi, Michele

AU - Lauritzen, Pernille

AU - Joseph, Oveen M.

AU - Asao, Tetsuhiko

AU - Grandgenett, Paul M.

AU - Hollingsworth, Michael A.

AU - Peralta, Christopher

AU - Pagano, Alexandra E.

AU - Molina, Henrik

AU - Lengel, Harry B.

AU - Dunne, Elizabeth G.

AU - Jing, Xiaohong

AU - Schmitter, Madeleine

AU - Borriello, Lucia

AU - Miller, Thomas

AU - Zhang, Haiying

AU - Romin, Yevgeniy

AU - Manova, Katia

AU - Paul, Doru

AU - Remmel, H. Lawrence

AU - O'Reilly, Eileen M.

AU - Jarnagin, William R.

AU - Kelsen, David

AU - Castellino, Sharon M.

AU - Giulino-Roth, Lisa

AU - Jones, David R.

AU - Condeelis, John S.

AU - Pascual, Virginia

AU - Bussel, James B.

AU - Boudreau, Nancy

AU - Matei, Irina

AU - Entenberg, David

AU - Bromberg, Jacqueline F.

AU - Simeone, Diane M.

AU - Lyden, David

PY - 2025/3/20

Y1 - 2025/3/20

N2 - 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 αX 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.

AB - 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 αX 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.

KW - cancer

KW - cancer metastasis

KW - cancer-associated thrombosis

KW - extracellular vesicles

KW - integrin beta 2

KW - platelets

KW - pro-thrombotic niche

UR - http://www.scopus.com/inward/record.url?scp=86000363293&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2025.01.025

DO - 10.1016/j.cell.2025.01.025

M3 - Article

C2 - 39938515

AN - SCOPUS:86000363293

SN - 0092-8674

VL - 188

SP - 1642-1661.e24

JO - Cell

JF - Cell

IS - 6

ER -

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

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Keywords

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