Background: Activation of the coagulation cascade and platelets are hallmarks of cancer and recent evidence indicates that tumors induce profound alterations in platelet transcriptomes. However, underlying mechanisms that contribute to the transfer of tumor cell RNA to tumor educated platelets are incompletely understood. We hypothesized that hypercoagulability contributes to platelet transcriptome changes in tumor bearing mice.

Aims: We determined tumor-induced platelet transcriptome alterations in WT and hyperthrombotic, thrombomodulin mutated TM^Pro mice. We also deleted PAR4 to assess the role of thrombin signaling in tumor education of platelets.

Methods: We characterized in transplanted tumor models tumor cell expressed genes, composition of the tumor microenvironment, and platelet transcriptomes by next generation sequencing and quantitative real time PCR.

Results: Tumor growth rates were similar in all mouse strains with no apparent differences in immune cell infiltration of the tumor microenvironment. Spontaneous lung metastasis was increased in hyperthrombotic TM^Pro mice, but metastasis was low and similar to wild-type mice in TM^Pro/PAR4^-/- with abolished platelet thrombin signaling. Platelet counts were lower in tumor bearing compared to tumor free animals. In contrast to markedly increased platelet consumption in hyperthrombotic TM^Pro mice, platelet counts of TM^Pro/PAR4^-/- did not change upon tumor implantation. We detected 200-300 transcript changes in platelets from tumor-bearing TM^Pro mice relative to tumor free animals as well as in comparisons of tumor bearing TM^Pro or TM^Pro/PAR4^-/- mice with wild-type. Approximately 70% of these transcripts were also found in isolated tumor cells or primary tumors, indicating that the RNA species are tumor derived.

Conclusions: Hyperthrombotic mice have alterations in platelet transcriptomes in comparison to tumor bearing wild-type mice. The majority of these platelet transcriptome changes can be traced to tumor cell transcripts and appear to occur independent of platelet hyperreactivity in tumor bearing hosts.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/tumor-platelet-transcriptome-changes-in-hyperthrombotic-mice/