Name: Eugene Tulchinsky
Department of Biomedical Sciences
Tumour cell plasticity and hallmarks of cancer.
PhD projects are available in cancer research area.
The main hurdle in anti-cancer therapy is tumour heterogeneity, a phenomenon driven by two factors, genetic diversity and reversible phenotypic plasticity. Gene mutations occur stochastically in cells within tumour tissue generating genetic diversity, and providing material for clonal selection and expansion. This process is fueled by the mutations in genes safeguarding genome integrity, so-called “caretaker tumour suppressor genes”. Some of these mutations lead to the formation of tumour cell populations featuring high phenotypic plasticity. Phenotypic plasticity encompasses different aspects of cancer cell biology including phenotypic transformation per se, reversible transition from the proliferative towards migratory and invasive phenotypes, metabolic reprogramming. Importantly, drug resistance is also a plastic property of cancer cells, and presence of slowly proliferating drug-resistant tumour cells explains the phenomenon of the residual disease. Moreover, these cells are responsible for cancer recurrence many years after the initial treatment.
Phenotypic plasticity is regulated by reversible epithelial mesenchymal (EMT) and mesenchymal epithelial transition (MET) genetic programs. In the course of EMT, cells lose their epithelial characteristics, apicobasal polarity, intercellular adhesion complexes and cytoskeletal architecture specific for epithelial tissues. Concurrently, cells acquire mesenchymal type of cell polarity, and the invasive capacity. EMT/MET programs affect most if not all hallmarks of cancer, cell cycle control, drug resistance, immune evasion, stemness, etc. Plastic nature of tumour cells postulates that they do not undergo terminal differentiation, but rather remain in intermediate stages.
It is becoming evident that targeting EMT/MET-dependent tumour cell plasticity will provide a unique opportunity to improve the efficacy of existing therapies. We offer several PhD projects centered on the characterization of potentially targetable molecular pathways implicated in EMT/MET plasticity and drug resistance. The focus will be on the molecules (such as transcription factor FRA1 and receptor tyrosine kinase AXL) previously shown to regulate EMT/MET balance and resistance to targeted and conventional therapies. Another type of projects will focus on the interrelationship between EMT and the expression and function of caretaker tumour suppressors. The aim of these projects is to investigate whether tumour cell plasticity can be targeted via synthetic lethality approaches.