Omics Analysis of Educated Platelets in Cancer and Benign Disease of the Pancreas

Simple Summary: Tumor cells are known to produce and secrete pro-coagulants that recruit blood particles such as platelets, inducing hypercoagulability. However, platelets can also influence tumor carcinogenesis and metastasis, creating a reciprocal, vicious loop with the tumors. Confrontation of platelets with tumor cells via transfer of tumor-associated biomolecules or influencing platelets biology (education) is an emerging concept, that has been recently proposed to create innovative platforms for biomarkers within blood-based liquid biopsies. In this study, we explore the intrinsic regulation and the potential education of platelets using -omics profiling in pancreatic cancer patients. Our results showed: (i) a high activity on RNA splicing that can lead to subsequent platelets education; (ii) enrichment of specific modified forms (isomiRs) of canonical miRNAs; and (iii) inhibition of SPARC transcription by specific class of isomiRs. Moreover, we created an interactive tool to visualize expected correlations, to facilitate further investigations on additional potential biomarkers and therapeutic tools. Pancreatic ductal adenocarcinoma (PDAC) is traditionally associated with thrombocytosis/hypercoagulation and novel insights on platelet-PDAC dangerous liaisons are warranted. Here we performed an integrative omics study investigating the biological processes of mRNAs and expressed miRNAs, as well as proteins in PDAC blood platelets, using benign disease as a reference for inflammatory noise. Gene ontology mining revealed enrichment of RNA splicing, mRNA processing and translation initiation in miRNAs and proteins but depletion in RNA transcripts. Remarkably, correlation analyses revealed a negative regulation on SPARC transcription by isomiRs involved in cancer signaling, suggesting a specific education in PDAC platelets. Platelets of benign patients were enriched for non-templated additions of G nucleotides (#ntaG) miRNAs, while PDAC presented length variation on 3 ' (lv3p) as the most frequent modification on miRNAs. Additionally, we provided an actionable repertoire of PDAC and benign platelet-ome to be exploited for future studies. In conclusion, our data show that platelets change their biological repertoire in patients with PDAC, through dysregulation of miRNAs and splicing factors, supporting the presence of de novo protein machinery that can educate the platelet. These novel findings could be further exploited for innovative liquid biopsies platforms as well as possible therapeutic targets.

Automated summary

Tumor cells can affect the biology of platelets, leading to high activity in platelet education-related RNA splicing, enrichment of specific modified forms of guiding miRNAs, and inhibition of SPARC transcription by specific isomiRs. These findings provide potential for innovative liquid biopsy platforms and therapeutic targets.