Supervisor View Full Details 2nd

• cancer/oncology
• Other

Senescence, Chemoresistance, Extracellular Vesicles/exosomes, Breast Cancer

• Medicine
• Surgery
• Pathology

• Oncology

Amanda McCann is a PI and UCD Conway Fellow in the UCD Conway Institute of Biomolecular and Biomedical Science. She is also Associate Professor and Head of Pathology in the UCD School of Medicine and Academic Lead on the establishment of the UCD Academic Centre in Translational Oncology (ACTO). She is also a founding member of the International Cell Senescence Association (ICSA) http://www.cellsenescence.info/

Her group's specific area of interest is to decipher how cancer cells can maintain viability via cellular senescence in the face of chemotherapy, particularly in the space of triple negative breast cancer and high grade serous ovarian cancer. Cellular senescence is a viable cellular fate mechanism which although non-replicative, is highly metabolically active producing a wealth of cytokines and an increased release of extracellular vesicles/exosomes that impact directly on the tumour microenvironment (TME). Tumour hypoxia integral to chemoresistance and indeed chemotherapeutic agents such as the taxanes and platinums used in the portfolio of drugs in the TNBC and ovarian cancer setting can also induce senescence. Her group and others believe that the eradication of senescent cells will ensure a more efficacious patient response to chemotherapy.

Triple negative breast cancer (TNBC) is an aggressive, innately hypoxic and chemoresistant tumour with a poor clinical outcome. Treatments are limited and non-specific, due to its treatment-resistant biology. Chemotherapy, while killing cancer cells, paradoxically also results in the generation of highly resistant viable senescent cancer cells which have the potential to form stem cell niches resulting in metastatic disease. Importantly, both hypoxic environments and senescent cells release considerably more extracellular vesicles (EVs) /exosomes than normoxic or non-senescent cells.

Hypothesis:- Extracellular Vesicle (EV) profiles generated from the plasma of patients with advanced /metastatic TNBC (mTNBC), can predict treatment response and patient outcome and potentially identify novel treatment targets in the advanced TNBC setting.

PhD Project Outline:-

1. Ethical approval has been granted by the Mater Hospital Dublin, Ireland, to obtain longitudinal plasma samples from women diagnosed with mTNBC. Five samples will be obtained during the course of a year of the patient's treatment journey. Recruitment has already commenced including detailed clinical response information recorded.

2. Following extravesicle/exosome (EV) isolation from these clinical plasma samples
- Nanoparticle Tracking Analysis (NTA) will enumerate and size the number of EVs per sample and generate a differential size signature longitudinally compared to the patient-s initial sample.
- Raman spectroscopy will generate macromolecular signatures that we can longitudinally compare.
- HPLC glycosylation profiling and lectin binding arrays will identify an N-glyan signature on EV membranes which will be profiled longitudinally.
- Mass spectrometry differential protein analysis of the EV membrane and contents will also be profiled.

The later part of the Doctoral studies will involve targeting key extravesicle (EV) membrane proteins (using antibodies) and EV membrane glycan moieties (using lectins) to
1) Disrupt the ability of EVs to subsequently dock, internalise and share their transcriptional and nutritional load with recipient cancer cells.
2) As exosomal membrane profiles uniquely reflect the cell type from which they are derived, these profiles will give us insight into possible novel targets to treat mTNBC disease for which there is currently no long term cure.

Selected Publications:-
PMID:-26676166
PMID: 25684390
PMID: 20676051
PMID: 19584087