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

被引：8

作者：

Lucotti, Serena ^{[1
,2
,3
,4
]}

Ogitani, Yusuke ^{[1
,2
,3
,4
]}

Kanific, Candia M. ^{[1
,2
,3
,4
]}

Geri, Jacob ^{[5
]}

Kim, Young Hun ^{[6
]}

Gu, Jinghua ^{[3
,4
]}

Balaji, Uthra ^{[3
,4
]}

Bojmar, Linda ^{[1
,2
,3
,4
,7
]}

Shaashua, Lee ^{[1
,2
,3
,4
]}

Song, Yi ^{[8
]}

Cioffi, Michele ^{[1
,2
,3
,4
]}

Lauritzen, Pernille ^{[1
,2
,3
,4
]}

Joseph, Oveen M. ^{[1
,2
,3
,4
]}

Asao, Tetsuhiko ^{[1
,2
,3
,4
,9
,10
]}

Grandgenett, Paul M. ^{[11
]}

Hollingsworth, Michael A. ^{[11
]}

Peralta, Christopher ^{[12
]}

Pagano, Alexandra E. ^{[12
]}

Molina, Henrik ^{[12
]}

Lengel, Harry B. ^{[9
]}

Dunne, Elizabeth G. ^{[9
]}

Jing, Xiaohong ^{[13
]}

Schmitter, Madeleine ^{[13
]}

Borriello, Lucia ^{[15
,16
]}

Miller, Thomas ^{[1
,2
,3
,4
]}

Zhang, Haiying ^{[1
,2
,3
,4
]}

Romin, Yevgeniy ^{[6
]}

Manova, Katia ^{[6
]}

Paul, Doru ^{[17
]}

Remmel, H. Lawrence ^{[1
,2
,3
,4
,18
,19
]}

O'Reilly, Eileen M. ^{[20
]}

Janagin, William R. ^{[8
]}

Kelsen, David ^{[20
]}

Castellino, Sharon M. ^{[21
,22
]}

Giulino-Roth, Lisa ^{[23
]}

Jones, David R. ^{[9
]}

Condeelis, John S. ^{[24
,25
,26
,27
,28
,29
]}

Pascual, Virginia ^{[1
,2
,3
,4
]}

Bussel, James B. ^{[3
,4
,23
]}

Boudreau, Nancy ^{[1
,2
,3
,4
]}

Matei, Irina ^{[1
,2
,3
,4
]}

Entenberg, David ^{[25
,26
,27
,28
,29
,30
]}

Bromberg, Jacqueline F. ^{[31
,32
]}

Simeone, Diane M. ^{[14
,33
]}

Lyden, David ^{[1
,2
,3
,4
]}

机构：

[1] Weill Cornell Med, Childrens Canc & Blood Fdn Labs, Meyer Canc Ctr, Dept Pediat, New York, NY 10065 USA

[2] Weill Cornell Med, Childrens Canc & Blood Fdn Labs, Meyer Canc Ctr, Dept Cell & Dev Biol, New York, NY 10065 USA

[3] Weill Cornell Med, Drukier Inst Childrens Hlth, New York, NY 10065 USA

[4] Weill Cornell Med, Dept Pediat, New York, NY 10065 USA

[5] Weill Cornell Med, Dept Pharmacol, New York, NY USA

[6] Mem Sloan Kettering Canc Ctr, Mol Cytol Core Facil, New York, NY USA

[7] Linkoping Univ, Dept Biomed & Clin Sci, Linkoping, Sweden

[8] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY USA

[9] Mem Sloan Kettering Canc Ctr, Dept Surg, Thorac Surg Serv, New York, NY USA

[10] Juntendo Univ, Dept Resp Med, Tokyo, Japan

[11] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE USA

[12] Rockefeller Univ, Prote Resource Ctr, New York, NY USA

[13] New York Univ Langone Hlth, Perlmutter Canc Ctr, New York, NY USA

[14] UC San Diego Hlth, Dept Surg, San Diego, CA 92121 USA

[15] Temple Univ, Lewis Katz Sch Med, Dept Canc & Cellular Biol, Philadelphia, PA USA

[16] Fox Chase Canc Ctr, Canc Signaling & Microenvironm Program, Philadelphia, PA USA

[17] Weill Cornell Med, Dept Med, Div Hematol & Med Oncol, New York, NY USA

[18] Atossa Therapeut Inc, Seattle, WA USA

[19] Univ Med Ctr Utrecht, Dept Pathol, Utrecht, Netherlands

[20] Mem Sloan Kettering Canc Ctr, Dept Med, Gastrointestinal Oncol Serv, New York, NY USA

[21] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA

[22] Childrens Healthcare Atlanta, Aflac Canc & Blood Disorders Ctr, Atlanta, GA USA

[23] Weill Cornell Med, Dept Pediat, Div Hematol Oncol, New York, NY USA

[24] Montefiore Med Ctr, Einstein Coll Med, Dept Surg, Bronx, NY USA

[25] Einstein Coll Med, Montefiore Med Ctr, Integrated Imaging Program Canc Res, Bronx, NY USA

[26] Einstein Coll Med, Montefiore Einstein Comprehens Canc Ctr, Montefiore Med Ctr, Bronx, NY USA

[27] Einstein Coll Med, Gruss Lipper Biophoton Ctr, Montefiore Med Ctr, Bronx, NY USA

[28] Einstein Coll Med, Montefiore Med Ctr, Dept Cell Biol, Bronx, NY USA

[29] Einstein Coll Med, Canc Dormancy Inst, Montefiore Med Ctr, Bronx, NY USA

[30] Einstein Coll Med, Montefiore Med Ctr, Dept Pathol, Bronx, NY USA

[31] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[32] Weill Cornell Med, Dept Med, New York, NY 10065 USA

[33] UC San Diego Hlth, Moores Canc Ctr, San Diego, CA 92121 USA

来源：

CELL | 2025年 / 188卷 / 06期

关键词：

cancer; cancer metastasis; pro-thrombotic niche; cancer-associated thrombosis; platelets; extracellular vesicles; integrin beta 2; DISSEMINATED INTRAVASCULAR COAGULATION; LYMPHOID-TISSUE IBALT; INTERSTITIAL MACROPHAGES; PANCREATIC-CANCER; CELL-CULTURE; MURINE LUNG; IN-VIVO; MICROPARTICLES; ACTIVATION; THROMBOEMBOLISM;

D O I：

10.1016/j.cell.2025.01.025

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 beta(2) that dimerizes with integrin alpha(X) and interacts with platelet-bound glycoprotein (GP)Ib to induce platelet aggregation. Blocking integrin beta(2) decreases both sEV-induced thrombosis and lung metastasis. Importantly, sEV-beta(2) 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-beta(2) as a prognostic biomarker of thrombosis risk as well as a target to prevent thrombosis and metastasis.

引用

页码：1642 / 1661.e24

页数：45

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