Glycoprotein Ibα-Dependent Platelet Activation is Essential for Tumor Cell–Platelet Interaction and Experimental Metastasis

Abstract

Metastasis is the main cause of cancer-related deaths and the biggest challenge in improving cancer prognosis. Platelet–tumor cell aggregates are a prerequisite for hematogenous metastasis. However, the internal relation and molecular mechanism of platelets and their receptor glycoprotein (GP) Ibα in platelet–tumor cell interaction and metastasis remain elusive. Here, we find that in the absence of the full-length GPIbα or its cytoplasmic tail, platelets maintain a more resting state and exhibit reduced tumor cell-induced platelet activation. The deficiency of the cytoplasmic tail of GPIbα inhibits tumor cell–platelet interaction, platelet-induced tumor cell migration and invasion, and metastasis. Using a state-of-the-art spinning disk intravital microscopy, we observe a rapid accumulation of platelets on tumor cells, forming numerous tumor cell–platelet aggregates in vivo. We also find that the cytoplasmic tail of GPIbα regulates the tumor cell-induced platelet protein kinase C-α (PKCα) activation, and both the pharmacological inhibition and genetic ablation of platelet PKCα attenuate tumor cell-induced platelet activation, tumor cell–platelet interaction, tumor cell migration and invasion, and metastasis. Overall, our findings reveal for the first time that GPIbα promotes experimental metastasis through its cytoplasmic tail-regulated platelet activation, and suggest a potential target to regulate tumor hematogenous metastasis.

Keywords

glycoprotein Ibα / metastasis / platelet activation / tumor cell–platelet interaction

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