Among the fundamental properties of cancer cells is they manufacture and release abnormally high levels of small vesicles. Most of these originate within multivesicular endosomes, which traffic and release pre-formed nano-vesicles into the pericellular space.
The intraluminal compartment of vesicles contains a cytosol-like fluid, but there is also active selection / enrichment of certain constituents. Vesicle biogenesis acts as a molecular sorting station, for fast tracking of selected components for expulsion. In the context of drug resistant cells, recent examples highlight the direct loading of chemotherapeutic agents into endosomal compartments, and into small vesicles, subsequently expelled from the cell. Here the intracellular drug dose is kept below toxic levels supporting resistance. An approach to supersensitise cells to the drug may involve attenuating vesicle expulsion pathway(s), but whether established drug resistance can be countered in this fashion is unknown. Sub-lethal drug insult also causes cellular stress, that is expected (like other forms of stress) to result in altered vesicle quantity, phenotype and subsequent vesicle-functions in microenvironmental communication. Studies of this nature are poorly developed from a vesicle perspective.
Our capacity to measure the drug loaded into expelled vesicles is of real interest; where longitudinal monitoring of high-drug load in plasma-derived vesicles may allow the emergence of treatment refractive cells to be detected much earlier in a non-invasive fashion.
The current proposal, therefore, brings together established capabilities in micro pharmacokinetics, drug design, vesicle biogenesis/secretion and analysis, to address the complex roles of vesicles in the cellular response to therapeutic agents.
We will test the hypothesis that vesicle production by cancer cells is an important mechanism underpinning drug resistance and that expelled drug-loaded vesicles can be utilised as a surrogate measure of cellular response to treatment. Important additional questions encompass the endogenous processes and their regulators that are required for this phenomenon, the vesicle generating pathways and vesicle sub-populations most relevant, and importantly the stress-imposed alterations on vesicle phenotype and subsequent vesicle functions in the microenvironment provide an additional dimension to the project, rife for exploration. The coming together of the Tissue MicroEnvironment Group supervisory team, bringing their track record in single cell micro-pharmacokinetics and exosome biology makes this a project that is novel, and uniquely possible at the School of Medicine.
We are seeking enthusiastic and motivated students with an interest in Cancer or genomic research. Applicants should possess a minimum of an upper second-class Honours degree, master's degree, or equivalent in a relevant subject.
Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS)
The total duration of this PhD programme is 3 years. Following discussion with proposed supervisors and to be considered you must submit a formal application via Cardiff University’s online application service. Medicine - Study - Cardiff University
There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (i.e. October 2022). This will take you to the application portal.
In the ‘Research Proposal’ section of the application enter the name of the project you are applying to.
Candidates must submit the following information:
- Supporting statement
- Qualification certificates
- Proof of Funding i.e. a letter of intent from your sponsor or confirmation of self-funded status.
- References x 2
- Proof of English language (if applicable)
Closing date for applicants is the 31st March 2022.