OC 66.3 - The Lung Pro-thrombotic Niche Drives Cancer-Associated Thromboembolism via Exosomal ITGB2

Tuesday, July 12, 2022

3:15 PM – 3:30 PM

Location: ExCel Center, ICC Capital Suite Room 10&11

Presentation Format: Virtual

Presenting Author(s)

Serena Lucotti, PhD

Postdoctoral Associate
Weill Cornell Medicine
New York, New York, United States

Co-Author(s)

YO

Yusuke Ogitani

Researcher Scientist
Daiichi-Sankyo Co., LTD
Tokyo, Tokyo, Japan
CK

Candia M. Kenific

Postdoctoral Associate
Weill Cornell Medicine
New York, New York, United States
LB

Linda Bojmar

Postdoctoral Associate
Weill Cornell Medicine
New York, New York, United States
MC

Michele Cioffi

Postdoctoral Associate
Weill Cornell Medicine
New York, New York, United States
PL

Pernille Lauritzen

Research Staff
Weill Cornell Medicine
New York, New York, United States
HM

Henrik Molina

Proteomic Core Director
The Rockefeller University
New York, New York, United States
SH

Soeren Heissel

Research Staff
The Rockefeller University
New York, New York, United States
HL

Harry B. Lengel

Research Fellow
Memorial Sloan Kettering Cancer Center
New York, New York, United States
XJ

Xiaohong Jing

Research Project Manager
New York University Langone Health
New York, New York, United States
HZ

Haiying Zhang

Assistant Professor
Weill Cornell Medicine
New York, New York, United States
IM

Irina Matei

Assistant Professor
Weill Cornell Medicine
New York, New York, United States
EO

Eileen M. O'Reilly

Medical Oncologist
Memorial Sloan Kettering Cancer Center
New York, New York, United States
WJ

William R. Jarnagin

Chief of Hepatobiliary Service
Memorial Sloan Kettering Cancer Center
New York, New York, United States
DJ

David R. Jones

Chief of Thoracic Service
Memorial Sloan Kettering Cancer Center
New York, New York, United States
JB

James B. Bussel

Professor Emeritus
Weill Cornell Medicine
New York, New York, United States
DK

David Kelsen

Medical Oncologist
Memorial Sloan Kettering Cancer Center
New York, New York, United States
JB

Jacqueline F. Bromberg

Medical Oncologist
Memorial Sloan Kettering Cancer Center
New York, New York, United States
DS

Diane M. Simeone

Director of Pancreatic Cancer Center
New York University Langone Health
New York, New York, United States
DL

David Lyden

Professor in Pediatrics
Weill Cornell Medicine
New York, New York, United States

Background: Thromboembolism (TE) is a common complication in cancer patients, especially at the metastatic stage, and the second leading cause of cancer-related deaths. The prevention of TE still remains an unmet clinical need due to the lack of predictive biomarkers and the bleeding risk associated with routine anti-coagulants.

Aims: Our aim is to dissect the role of exosomes as initiator of cancer-associated TE, in order to develop exosome-based markers for TE risk and targets for TE prevention.

Methods: Exosomes were isolated from tissues of mice with melanoma (B16F10), breast cancer (MMTV-PyMT), lung cancer (Lkb1-/- KrasG12D/WT), and PDAC (KPC), or cell lines. The pro-thrombotic effect of exosomes was studied in vivo (platelet count, D-Dimer, platelet/fibrin staining), and in vitro (LTA and flow cytometry).

Results: We found that exosomes from pre-metastatic and metastasis-bearing lungs of tumor-bearing mice induce extensive pulmonary embolism in naïve mice and package high levels of integrin beta 2 (ITGB2). Instead, exosomes from normal lungs, cell lines, tumors, or other metastasis-bearing organs did not show any pro-thrombotic properties. Monocytes/macrophages infiltrating pre-/post-metastatic lungs were the main source of ITGB2+ exosomes. We found that ITGB2 interacts directly or through fibrin with different platelet ligands, and induce their activation and aggregation. Importantly, blockade of ITGB2 on lung exosomes or systemically in mice prevented exosome-induced platelet aggregation and TE. Finally, we showed that exosomal ITGB2 levels are elevated in the plasma of Stage IV PDAC patients prior to TE events in comparison to patients with no history of TE.

Conclusion(s): We provide the first evidence of the establishment of a pro-thrombotic lung niche in different cancer types. We have identified exosomal ITGB2 as a new target for the prevention and/or treatment of TE, as well as a potential “liquid biopsy” analyte for the stratification of patients at high risk of TE.