PB0732 - Fibrin Promotes Glioblastoma Progression via Focal Adhesion Kinase

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Co-Author(s)

LK

Lynn M. Knowles

Research Instructor
Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University School of Medicine and Saarland University Medical Center
Homburg, Saarland, Germany
Carolin Wolter, MSc

PhD Student
Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University School of Medicine and Saarland University Medical Center
Homburg, Saarland, Germany
RK

Ralf Ketter

Professor
Departement of Neurosurgery
Homburg, Saarland, Germany
SU

Steffi Urbschat

Professor
Departement of Neurosurgery
Homburg, Saarland, Germany
SL

Stefan Linsler

Deputy Director
Departement of Neurosurgery
Homburg, Saarland, Germany
SM

Simon Müller

Consultant
Departement of Neurosurgery
Homburg, Saarland, Germany
AM

Andreas Müller

Scientific Assistant
Departement of Radiology
Homburg, Saarland, Germany
XZ

Xiangda Zhou

Scientific Assistant
Biophysics
Homburg, Saarland, Germany
BQ

Bin Qu

Working Group Leader
Biophysics and INM-Leibniz Institute for New Materials
Homburg, Saarland, Germany
HE

Hermann Eichler

Professor of Transfusion Medicine and Haemostaseology
Institute of Clinical Haemostaseology and Transfusion Medicine, University and University Hospital of the Saarland, Homburg, Germany
Homburg, Saarland, Germany

Presenting Author(s)

Jan Pilch, MD

Assistant Professor
Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University School of Medicine and Saarland University Medical Center
Homburg, Saarland, Germany

Background: Glioblastoma (GBM) is a highly aggressive brain tumor characterized by invasive growth and the leakage of a fibrin-rich edema into tumor interstitial spaces from poorly organized tumor blood vessels.

Aims: To test if clotted plasma supports GBM progression.

Methods: We assessed fibrin formation in astrocytoma samples from patients using immunohistochemistry and examined the effect of plasma clot on glioblastoma growth in mice in vivo. Glioblastoma cells embedded in 3-D fibrin were analyzed for invasion and growth using live cell imaging and deconvolution microscopy. In order to assess clinical relevance, we analyzed primary cells and tissue arrays.

Results: We demonstrate a marked upregulation of clot formation in the interstitial spaces of astrocytoma patients while tumor-free brain is essentially devoid of fibrin. This is relevant as we detected a delay of glioblastoma development in clotting-deficient hemophilia mice and accelerated tumor growth in nude mice after implanting glioblastoma cells in conjunction with clotted plasma. This growth promoting effect was reproducible when we cultured GBM cells in a 3-dimensional matrix of clotted plasma in vitro. The pro-growth effect of the clotted plasma resulted from adhesive interactions with integrins on GBM cells, which in turn promoted the activation of focal adhesion kinase and p42/Erk. In addition, engagement of integrins promoted the formation of actin-rich invadopodia and subsequent locomotion of GBM cells. Invadopodia formation in clotted plasma was also evident in primary tumor cells from patients with astrocytoma 2 and 3 but only primary GBM cells were able to grow sufficiently in 3D clot. Finally, overexpression of focal adhesion kinase-activating integrins in glioma tissues from patients was associated with a significantly decreased overall survival.

Conclusion(s): The deposition of clotted plasma in tumor interstitial spaces promotes infiltration and proliferation of glioblastoma cells and, therefore, may provide a therapeutic target to combat primary brain tumors.