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.
© 2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.
