Supervisor View Full Details

Supervisor View 2
October 3, 2016
Supervisor View Full Details 2nd
October 12, 2016

Prof John O'Leary

Department:Dept of Histopathology

Division:Medicine

Organisation:Trinity College Dublin

Webpage:https://medicine.tcd.ie/histopathology/

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Research Fields
  • cancer/oncology
Postgrad Medical Specialites
  • Pathology
Medical Subspecialties
  • Immunology
My Work

Our lab group based in Trinity College Dublin with satellite researchers at the National Cancer Registry, Cork and Dublin City University is composed of 40 research scientists working in pre-cancer and cancer in the following areas: cervical, ovarian, head and neck and prostate cancer, cancer metastasis, cancer stem cell biology, cancer genomics, transcriptomics and proteomics, autologous cancer cell vaccination, devices, nanomedicine and nanorobotics. The group has already brought 43 students to successful completion of their PhD degree.

The laboratory has a full suite of state-of-the-art molecular biology facilities including: next generation sequencing facilities [Ion Torrent and Illumina], cloning, transfection, gene knock-down [including CRISPR/Cas 9 gene editing], automated immunocytochemistry, spectral karyoptyping, array CGH, Affymetrix sequencing, histotechnology and cell culture.

Potential Projects

Metastasis is the deadliest aspect of cancer and the single most significant challenge to the management of the disease.

Cancer metastasis is a distinct, complicated, multi-step process with its own dynamics. It involves a cell or group of cells exiting the primary tumour, through the induction of epithelial-mesenchymal-transition [EMT], and intravasating into the vascular system, where they are known as circulating tumour cells (CTCs). We have identified CTCs as single cells, groups of cells [morules], cells coated with blood components [platelets] and microemboli.

We have demonstrated a universal, potent and dynamic interaction between platelets and cancer cells, which aids survival and drives a pro-metastatic phenotype in the cancer cells, through the induction of EMT, cancer cell invasion and stem cell plasticity. This work has lead to the identification of a 34 signature gene panel that defines significant effector molecules of the platelet?s pro-metastatic drive.

Understanding how CTCs survive in the circulation by evading natural immune responses is central to establishing which CTCs are biologically relevant to metastasis and therefore, clinically relevant. We have demonstrated that platelet cloaking significantly decreases NK cell activity towards cancer cells via the modulation of the NK cell tumour recognition systems NKG2D-MICA/MICB and CD96/CD226-CD155/CD112. Activated platelets on the CTC surface induce the shedding of the NKG2D receptor agonistic ligand, MICB, from tumour cells into the tumour microenvironment and general circulation, eliciting an ?immune decoy? mechanism.

Platelet-derived TGF? suppresses expression of CD226 (DNAM-1), an activating receptor on NK cells. Platelets and platelet derived factors potently reduce CD96 receptor expression on NK cells, making these novel markers in cancer cell metastasis.

The second limb of immune surveillance involves monocytes/macrophage-cancer cell interactions. M1 macrophages have pro-inflammatory and anti-cancer functions, while M2 macrophages are immunosuppressive, contributing to the matrix-remodelling, and hence favouring tumour growth. We have demonstrated that platelet cloaking of cancer cells results in ?education? of monocytes: from an M0 phenotype to an M2 phenotype.

This proposed study involves molecular dissection of the interaction between platelets and cancer cells in the metastatic cascade, to more completely understand the basis for platelet-induced cancer cell survival and evasion of immune surveillance.