Dr Christina Nedeva is a member of the Mathivanan group at the La Trobe Institute for Molecular Science (LIMS). The group seeks to identify novel mechanisms regulating the biogenesis of extracellular vesicles (EVs) through collaboration with the Research Centre for Extracellular Vesicles (RCEV). The group has also developed methods for effectively loading EVs with cancer fighting agents for therpeutic development strategies against breast cancer.
Dr Nedeva hold a Victorian Cancer Agency (VCA) Early Career Fellowship.
Research areas
Understanding the mechainsms involved in EV biogenesis and utilising EVs for drug delivery
EVs are small membrane-bound structures released by virtually all cells that function in intercellular communication. Currently, a large body of evidence suggests that many cancer cell types release higher amounts of EVs compared to healthy cells. Additionally, it has been shown that cancer cell-derived EVs transfer bioactive molecules allowing cancer to establish pre-metastatic niches at distant sites in the body. However, cargo sorting and biogenesis of EVs are poorly understood.
Using proteomic analysis of EVs, we have identified caspase substrates that participate in EV biogenesis. Our results showed that cells lacking caspase 3 or 7 produced fewer EVs compared to WT cell-derived EVs. These findings attributed a novel function for executioner caspases in EV biogenesis. Furthermore loss of caspases modified the protein cargo of small and large extracellular vesicles. In addition, we showed that caspases regulate multivesiclular body (MVB) formation via interactions with the ER degradation (ERAD) pathway. These findings allow us to better understand how these processes work and how they may regulate pathology.
Leveraging our expertise in EV isolation and cargo loading in EVs, we have succesfully developed methods for loading anti-cancer agents into EVs for delivery to breast cancer. These loaded EVs hold promise as putative therpies against cancer as the vehicles have shown cancer fighting protperties in mouse models.
Identifying and therpeutically targeting mediators involved in cancer cachexia
Cancer cachexia is a severe multi-tissue wasting syndrome that largely effects skeletal muscle and adipose tissue. It is often an indicator of “end of life”, presenting in approximately 65% of all cancer patients, mostly during the advanced stages of disease. Compounding the devastating physical effects of the cancer itself, cachexia drastically alters a person’s body image which has detrimental psychological implications on the patient as well as people around them, such as caregivers. Due to the rapid physical deterioration associated with cancer cachexia, approximately 35% of patients will die as they are too weak to maintain life-saving anti-cancer treatment. At present, there are no guidelines for the treatment of cancer cachexia. Patients are generally given appetite stimulants such as glucocorticoids and megestrol, which improve caloric intake but have no functional benefit. Therefore, treating cancer cachexia remains one of the biggest challenges in the clinic.
In our lab we aim to identify factors involved in cancer cachexia and develop therapies against this heterogenous syndrome, whilst gaining an understanding of the complex interplay between tumour and host factors. To date we have found that loss of an actin binding protein in cachexia causing cancer cells prevented lipolysis, muscle atrophy and substantially improved the overall wellbeing of our mouse models. More recently, we have also identified FDA approved drugs that are able to reduce the expression of the actin binding protein in vitro. Our studies provide a novel role for this protein in the aetiology of cancer induced weight loss and indicate that blocking this protein may be a promising approach to treat cancer cachexia, improving quality of life and extend lifespan of cancer patients.
