OC 28.2 - Platelet β1 and β3 integrins are essential for hemostasis, arterial thrombosis and tumor metastasis

Sunday, June 23, 2024

15:00 – 15:15 ICT

Room: 211 A-D

Presenting Author(s)

Emily Janus-Bell, PhD

Research scientist
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France

Co-Author(s)

CL

Cristina Liboni

Postdoc
INSERM UMR_S1109, Tumor Biomechanics Lab, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), CNRS, SNC5055, Strasbourg, France
Strasbourg, Alsace, France
AY

Alexandra Yakusheva

Postdoc
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France
VM

Vincent Mittelheisser

PhD student
INSERM UMR_S1109, Tumor Biomechanics Lab, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), CNRS, SNC5055, Strasbourg, France
Strasbourg, Alsace, France
LB

Louis Bochler

PhD student
INSERM UMR_S1109, Tumor Biomechanics Lab, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), CNRS, SNC5055, Strasbourg, France
Strasbourg, Alsace, France
CM

Clarisse Mouriaux

Technician
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France
CB

Catherine Bourdon

Technician
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France
MG

Maria Garcia-Leon

Postdoc
INSERM UMR_S1109, Tumor Biomechanics Lab, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), CNRS, SNC5055, Strasbourg, France
Strasbourg, Alsace, France
VH

Vincent Hyenne

Research Director
INSERM UMR_S1109, Tumor Biomechanics Lab, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), CNRS, SNC5055, Strasbourg, France
Strasbourg, Alsace, France
OL

Olivier Lefebvre

Research Director
INSERM UMR_S1109, Tumor Biomechanics Lab, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), CNRS, SNC5055, Strasbourg, France
Strasbourg, Alsace, France
JG

Jacky Goetz

Research Director
INSERM UMR_S1109, Tumor Biomechanics Lab, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), CNRS, SNC5055, Strasbourg, France
Strasbourg, Alsace, France
PM

Pierre H. Mangin, PhD

Researcher
University of Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, Strasbourg, France
Strasbourg, Alsace, France

Background: Platelets express five distinct integrin pairs, namely α2β1, α5β1, α6β1, αvβ3 and αIIbβ3. All integrins regulate stable platelet adhesion and platelet aggregation. They contribute to various extents to hemostasis, arterial thrombosis and tumor metastasis. To date, the consequence of the combined absence of all integrins on platelet functions has never been investigated, and could help to better appreciate their overall importance.

Aims: The aim of the study was to characterize the contribution of integrins to platelet functions in hemostasis, thrombosis, tumor growth and metastasis.

Methods: We generated the first mouse strain fully devoid of integrin expression in platelets using the PF4Cre/lox recombination system (PF4Cre-β1-/-/β3-/-). We performed an in-depth characterization of mouse platelets using aggregometry, flow cytometry, flow based-assays, and experimental models of hemostasis and thrombosis. Orthotopic and metastasis models combined to in vivo imaging were used to assess tumor growth and metastasis.

Results: PF4Cre-β1-/-/β3-/- mouse platelets presented a normal expression of the main platelet surface receptors, apart from integrins, and responded normally to soluble agonists. In sharp contrast, PF4Cre-β1-/-/β3-/- platelet adhesion under flow was abrogated on adhesive proteins such as immobilized fibrinogen and fibrillar fibronectin. As a consequence, PF4Cre-β1-/-/β3-/- mice presented a dramatic increase in tail-bleeding time. Thrombus formation was also blocked in a blood flow assay, and in two experimental models of arterial thrombosis. Tumor growth was significantly reduced in PF4Cre-β1-/-/β3-/- subjected to an orthotopic syngeneic tumor model of triple-negative breast cancer. While depletion of platelet integrins had no or little impact on lung metastasis in that model, they profoundly impacted the myeloid populations of growing metastatic foci. When subjected to an experimental metastasis assay, mice deficient in platelet integrins showed a significantly reduced metastatic burden.

Conclusion(s): These results highlight the central role of integrins in platelet hemostatic functions, experimental thrombosis, and tumor growth and metastasis.