Platelets Promote Metastasis via Binding Tumor CD97 Leading to Bidirectional Signaling that Coordinates Transendothelial Migration

Abstract

Tumor cells initiate platelet activation leading to the secretion of bioactive molecules, which promote metastasis. Platelet receptors on tumors have not been well-characterized, resulting in a critical gap in knowledge concerning platelet-promoted metastasis. We identify a direct interaction between platelets and tumor CD97 that stimulates rapid bidirectional signaling. CD97, an adhesion G protein-coupled receptor (GPCR), is an overexpressed tumor antigen in several cancer types. Purified CD97 extracellular domain or tumor cell-associated CD97 stimulated platelet activation. CD97-initiated platelet activation led to granule secretion, including the release of ATP, a mediator of endothelial junction disruption. Lysophosphatidic acid (LPA) derived from platelets induced tumor invasiveness via proximal CD97-LPAR heterodimer signaling, coupling coincident tumor cell migration and vascular permeability to promote transendothelial migration. Consistent with this, CD97 was necessary for tumor cell-induced vascular permeability in vivo and metastasis formation in preclinical models. These findings support targeted blockade of tumor CD97 as an approach to ameliorate metastatic spread.

Drug Targeting via Platelet Membrane–Coated Nanoparticles

“…[52,53] Tumor cells also form thrombi with platelets for enhanced vascular adhesion and transendothelial migration. [54,55] During the metastasis, tumor cells shield themselves by attaching to platelets for protection against shear forces and immune attack, therefore increasing the chance of metastasis formation. [56,57] Tumor cells achieve such binding interactions by overly expressing ligands such as podoplanin, P-selectin PSGL-1, A disintegrin and metalloproteinase domain-containing protein 9 (ADAM-9), and fibrinogen/αvβ3.…”

Platelet count correlates with stage and predicts survival in melanoma

“…Platelets also propagate tumor cell metastasis independent of natural killer cells [9]. CD97 on cancer cells activates platelets to release lysophosphatidic acid (LPA), thus facilitating trans-endothelial migration [10]. We have also shown that platelets activate TGFβ and suppress anti-tumor T lymphocytes, thus aiding in melanoma growth [11].…”

Chemokines and Chemokine Receptors: Orchestrating Tumor Metastasization

“…Platelet-derived growth factors confer a mesenchymal-like phenotype to tumor cells and open the capillary endothelium to support extravasation in distant organs. It has been recently shown that, by releasing Lysophosphatidic acid (LPA), known to induce tumor invasiveness via proximal CD97-LPAR heterodimer signaling, platelets support extravasation and establishment of metastatic cells in distant organs [180].…”