Platelet glycoprotein VI promotes metastasis through interaction with cancer cell-derived galectin-3.

Abstract

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, because its inhibition is protective in models of arterial thrombosis, with only minor effects on hemostasis. In this study, the genetic deficiency of platelet GPVI in mice decreased 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 supported that mouse, as well as human GPVI, had platelet adhesion to colon and breast cancer cells. Using a CRISPR/Cas9-based gene knockout approach, we identified galectin-3 as the major counterreceptor of GPVI on tumor cells. In vivo studies demonstrated that the interplay between platelet GPVI and tumor cell-expressed galectin-3 uses 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 revealed 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.

• Authors: Elmina Mammadova-Bach, Jesus Gil-Pulido, Edita Sarukhanyan, Philipp Burkard, Sergey Shityakov, Charlotte Schonhart, David Stegner, Katharina Remer, Paquita Nurden, Alan T Nurden, Thomas Dandekar, Laszlo Nehez, Magdolna Dank, Attila Braun, Diego Mezzano, Scott I Abrams, Bernhard Nieswandt
• Journal: Blood (Blood) Vol. 135 Issue 14 Pg. 1146-1160 (04 02 2020) ISSN: 1528-0020 [Electronic] United States
• PMID: 32040544 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by The American Society of Hematology.

Chemical References

• Galectin 3
• Platelet Membrane Glycoproteins
• platelet membrane glycoprotein VI

Topics

• Animals
• Blood Platelets (metabolism, pathology)
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Cell Movement
• Colonic Neoplasms (metabolism, pathology)
• Female
• Galectin 3 (metabolism)
• Humans
• Lung Neoplasms (pathology, secondary)
• Male
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Neoplasm Metastasis (pathology)
• Platelet Activation
• Platelet Membrane Glycoproteins (genetics, metabolism)
• Protein Interaction Maps