Platelet RNA signatures for the detection of cancer

Abstract

Platelets are equipped with RNA processing machineries, such as pre-mRNA splicing, pre-miRNA processing, and mRNA translation. Since platelets are devoid of a nucleus, most RNA transcripts in platelets are derived from megakaryocytes during thrombocytogenesis. However, platelets can also ingest RNA molecules during circulation and/or interaction with other cell types. Since platelets were first described by Bizzozero in 1881, their well-established role in hemostasis and thrombosis has been intensively studied. However, in the past decades, the list of biological processes in which platelets play an important role keeps expanding. In this review, we discuss how platelet RNA biomarker signatures can be altered in the presence of cancer.

Keywords: Biomarkers; Liquid biopsy; Platelets; Splicing; Transcriptome; Tumor-educated platelets; mRNA.

Figures

Fig. 1

Schematic representation of tumor-mediated education of platelets and the megakaryocyte leading to metastasis. (a) Megakaryocytes in the bone marrow and lungs sort specific RNA and proteins into platelet precursors. (b) Circulating platelets contain a variety of RNA transcripts and proteins. During their 7–10-day lifespan, platelets interact with immune cells, cancer cells, and stromal cells. These direct interactions as well as distant cell signaling, for instance, via vesicle-mediated communication in whole blood, changes the content of the platelet and platelet function. (c) This process leads to the development of tumor-educated platelets. Next, tumor-educated platelets can influence the process of metastasis formation by stimulating or blocking immune cells, endothelial cells, stromal cells, and cancer cells, either by direct cell-to-cell contact or by releasing extracellular queues. (d) Finally, metastasis could affect the sorting of specific RNA and proteins of megakaryocytes into platelets

Fig. 2

ThromboSeq workflow. (a) TEP mRNA sequencing workflow; blood draw is performed on patients, and from a single 6-ml EDTA-coated tube, platelets are isolated. RNA extraction is done according to manufacturer’s protocol using the mirVana RNA isolation kit (Life Technologies). Next, mRNA is amplified using SMARTer Ultra low input RNA kit (Clontech). Samples are prepared for sequencing on the Hiseq 2500 Illumina platform using the Truseq Nano DNA Sample Prep Kit (Illumina). After each step, quality control was performed by critical inspection of Bioanalyzer profiles (Agilent). (b) Heatmap of unsupervised clustering of platelet mRNA profiles of healthy donors (red, n = 55) and patients with cancer (gray, n = 228)

Fig. 3

Correlation plots of TEP RNA signatures with other (a) nucleated blood cells. Correlation plots between platelets sequenced by Best et al. compared with platelet RNA expression levels from different studies and compared with RNA expression from different blood cells. (a) Platelets from Bray et al. [82]. (b) Poly A selected RNAs from platelets from Kissopoulou et al. [83]. (c) Ribosomal RNA-depleted platelets from Kissopoulou et al. [83]. (d) Platelets from Rowley et al. [84]. (e) Platelets from Simon et al. [85]. (f) Megakaryocyte [86]. (g) Memory T-cells [87]. (h) CD4 T-cells [87]. (i) CD8 T-cells [87]. (j) Granulocytes [87]. (k) B-cells [87]. (l) Monocytes [87]. (m) Natural killer cells [87]