Roles of mRNA Transfer in Cancer Cell-Platelet Communication

Abstract: The interaction between cancer cells and platelets plays important roles in regulating cancer cell function. Understanding how platelets communicate with cancer cells to modulate cancer cell colonization at distant organs may identify novel strategies to halt cancer spreading. We recently showed that recruitment of platelet to cancer cells is essential for circulating tumor cell (CTC) colonization at the secondary organs. However, the molecular mechanism by which binding of platelets modulates cancer cell function to promote cancer cell colonization remains to be determined. By analyzing single cell RNA-seq data from CTCs and primary tumors, we found that platelet-specific mRNA was significantly enriched in CTC. RNAscope and Translating Ribosome Affinity Purification (TRAP) analyses showed the delivery of platelet mRNA and translation of platelet-derived mRNA in cancer cells. In vivo functional screening identified multiple platelet-derived mRNAs contribute to colonization of breast cancer cell at distant organs. These results reveal the new role of platelet mRNA in mediating intercellular communication and in promoting cancer cell spreading. The overall objective of this proposal is to define the molecular mechanism by which platelet mRNA is delivered into breast cancer cells and determine roles of platelet mRNA as the signaling molecular in promoting cancer cell colonization at distant organs. We showed that CD9 expression in CTC correlated with the accumulation of platelet-specific mRNA. Silencing CD9 in breast cancer cells significantly reduced platelet mRNA transferring and colonization of cancer cells. Platelet factor 4 (PF4) is a small cytokine belonging to the CXC chemokine family that is highly expressed in platelets. We showed that the transfer of PF4 mRNA from platelets to breast cancer cells enhanced stemness and in vivo colonization of cancer cells. Based on these results, the central hypothesis of this proposal is that the CD9-dependent mRNA transfer mediates platelet-cancer cell communication and promotes cancer cell stemness. We propose the following two aims to test this hypothesis and achieve our objective. Aim 1. Elucidate the mechanism by which platelet mRNA is transferred into cancer cells. Aim 2. Determine how PF4 mRNA transferring from platelets promotes cancer cell colonization.