Cai Group - Cholangiocarcinoma epigenetics for target evaluation
- Shijie Cai
about the research
The focus of our group is to study the molecular mechanisms of tumour growth for biomarker identification and target development. One of the projects is investigating the epigenetics of cholangiocarcinoma (CCA), which is a rare malignant bile duct tumour (average incidence of 1/100,000 in the population per year). The overall incidence of CAA includes 15% of primary liver cancers, the second most common type of primary liver cancer, the majority of which are inoperable and resistant to chemotherapy. At present, the 5-year survival rate is less than 5%, therefore, there is an urgent need to identify novel mechanisms to facilitate early detection and novel therapy development.
We have recently reported that ubiquitin specific peptidase (USP)22 is one of crucial molecules regulating CCA progression (DOI: 10.1038/s41419-021-03940-0). USP22 can rewire the tumour development programme in the cell by modifying oncogenes to activate the survival signalling pathways. This occurs partially through epigenetic modulation, which stabilises oncoprotein histone structures, thus protecting tumour cells from apoptosis and maintaining survival. However, epigenetic dysregulation in CCA and the resultant resistance to therapy are still not well characterised.
An important area of investigation in this project is to understand the epigenetic mechanisms for regulating CCA apoptosis and cell survival. RNA sequencing and metabolomics will be used to determine the association between gene expression and the altered metabolic profile. Genetic manipulation can then be performed to evaluate key pathways and molecules in CCA development. Importantly, correlation of molecules with clinicopathology will be analysed in patient cohorts.
Another goal is to identify the epigenetic vulnerabilities of CCA by screening an epigenetic chemical probe library. The hit compounds will be assessed in 2D and 3D cultures. Genome editing for target validation will be conducted. Combination of inhibitors with chemotherapy will also be evaluated.
All these studies will be carried out in cell culture, animal model and human tumour tissues.
The student will acquire expertise in a wide range of state-of-the-art molecular and cell biological techniques, and bioinformatics analysis; finally providing an excellent foundation for a research career. Formalised training and assessment of each technique is carried out by members of the laboratory as needed. Our laboratory has clearly defined protocols to support training in specific experimental techniques. Standard operating procedures are regularly updated to ensure that methods are optimal to achieve good quality data and progress the project.
Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.
Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.
As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.
The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.
Additional supervision will be provided by Professor David Kerr
Tian Y. et al, Cell Death and Disease (2021)12:678