Platelet glycoprotein VI promotes metastasis through interaction with cancer cell-derived galectin-3
| Autor: | Elmina Mammadova-Bach, Charlotte Schonhart, Katharina A. Remer, Thomas Dandekar, Alan T. Nurden, Philipp Burkard, Paquita Nurden, Bernhard Nieswandt, Sergey Shityakov, Jesus Gil-Pulido, Diego Mezzano, Scott I. Abrams, Magdolna Dank, David Stegner, Attila Braun, Edita Sarukhanyan, Laszlo Nehez |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Blood Platelets Male Lung Neoplasms Galectin 3 Immunology Syk Breast Neoplasms Platelet Membrane Glycoproteins Biochemistry Metastasis 03 medical and health sciences 0302 clinical medicine Cell Movement Cell Line Tumor medicine Animals Humans Platelet Platelet activation Protein Interaction Maps Neoplasm Metastasis Mice Inbred BALB C Chemistry Cell Biology Hematology medicine.disease Platelet Activation Extravasation Mice Inbred C57BL 030104 developmental biology Galectin-3 Cancer cell Colonic Neoplasms Cancer research Female GPVI 030215 immunology |
| Zdroj: | Blood. 135(14) |
| ISSN: | 1528-0020 |
| Popis: | Increasing evidence suggests that platelets play a predominant role in colon and breast cancer metastasis but the underlying molecular mechanisms remain elusive. Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin that triggers platelet activation through immunoreceptor tyrosine-based activation motif (ITAM)-signaling and thereby regulates diverse functions including platelet adhesion, aggregation and procoagulant activity. GPVI has been proposed as a safe antithrombotic target as its inhibition is protective in models of arterial thrombosis with only minor effects on hemostasis. Here, we demonstrate that genetic deficiency of platelet GPVI in mice decreases experimental and spontaneous metastasis of colon and breast cancer cells. Similar results were obtained with mice lacking the spleen-tyrosine kinase Syk in platelets, an essential component of the ITAM-signaling cascade. In vitro and in vivo analyses show that mouse, as well as human GPVI, supports platelet adhesion to colon and breast cancer cells. Using a CRISPR/Cas9-based gene knock-out approach, we identified Galectin-3 as the major counter-receptor of GPVI on tumor cells. In vivo studies demonstrated that the interplay between platelet GPVI and tumor cell-expressed Galectin-3 utilizes ITAM-signaling components in platelets and favors the extravasation of tumor cells. Finally, we showed that JAQ1 F(ab)2-mediated inhibition of GPVI efficiently impairs platelet-tumor cell interaction and tumor metastasis. Our study reveals a new mechanism by which platelets promote the metastasis of colon and breast cancer cells and suggests that GPVI represents a promising target for antimetastatic therapies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|