Platelets reduce anoikis and promote metastasis by activating YAP1 signaling

Abstract

Thrombocytosis is present in more than 30% of patients with solid malignancies and correlates with worsened patient survival. Tumor cell interaction with various cellular components of the tumor microenvironment including platelets is crucial for tumor growth and metastasis. Although it is known that platelets can infiltrate into tumor tissue, secrete pro-angiogenic and pro-tumorigenic factors and thereby increase tumor growth, the precise molecular interactions between platelets and metastatic cancer cells are not well understood. Here we demonstrate that platelets induce resistance to anoikis in vitro and are critical for metastasis in vivo. We further show that platelets activate RhoA-MYPT1-PP1-mediated YAP1 dephosphorylation and promote its nuclear translocation which induces a pro-survival gene expression signature and inhibits apoptosis. Reduction of YAP1 in cancer cells in vivo protects against thrombocytosis-induced increase in metastasis. Collectively, our results indicate that cancer cells depend on platelets to avoid anoikis and succeed in the metastatic process.

Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis

“…Intriguingly, a recent study indicates that cancer cells depend on platelets to avoid anoikis and succeed in metastasis (47). Platelets induce resistance to anoikis in vitro and are critical for metastasis in vivo by activating RhoA-MYPT1-PP1-mediated YAP1 dephosphorylation and promoting its nuclear translocation to inhibit apoptosis.…”

Differential Effects of EGFL6 on Tumor versus Wound Angiogenesis

“…Western blot analysis was performed as previously reported (Pradeep et al, 2015, Haemmerle et al, 2017). Cell lysate of RF24 cells were treated with human recombinant EGFL6 protein or anti-EGFL6 antibodies and checked for activation of PI3kinase and AKT signaling by using anti-human EGFL6, PI3kinase, and AKT antibodies followed by secondary antibodies conjugated with horseradish peroxidase.…”

Platelets in chronic liver disease, from bench to bedside

“…32 Interestingly, the interaction between platelets and tumour cells was reported to be essential to avoid detachmentinduced apoptosis (anoikis), a major feature of metastasis. 33 Recently, platelet-derived TXA2 (which is generated by activated COX-1) was reported to promote a pro-metastatic niche involving endothelial cells, myeloid cells and tumour cells. 34 In this context, platelets can also produce pro-angiogenic and growth factors that facilitate tumour growth and survival, as well as promoting the metastatic potential of tumour cells.…”