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

Cell Rep. 2018 Apr 17;23(3):808-822. doi: 10.1016/j.celrep.2018.03.092.


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.

Keywords: CD97; LPA; adhesion GPCR; circulating tumor cells; metastasis; platelets; transendothelial migration.

MeSH terms

  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Blood Platelets / cytology
  • Blood Platelets / metabolism*
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Dimerization
  • Epidermal Growth Factor / pharmacology
  • Epithelial-Mesenchymal Transition
  • Humans
  • Lysophospholipids / pharmacology
  • Platelet Activation / drug effects
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Lysophosphatidic Acid / antagonists & inhibitors
  • Receptors, Lysophosphatidic Acid / metabolism
  • Signal Transduction*
  • Tight Junctions / metabolism
  • Transforming Growth Factor beta / metabolism


  • ADGRE5 protein, human
  • Antigens, CD
  • LPAR1 protein, human
  • Lysophospholipids
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled
  • Receptors, Lysophosphatidic Acid
  • Transforming Growth Factor beta
  • Epidermal Growth Factor
  • lysophosphatidic acid