A new approach to understanding the role of tumour microenvironment in anticancer drug resistance St George’s, University of London in United Kingdom

Melanoma is a type of skin cancer with the most rapidly growing incidence in the UK. In melanoma, like in many other cancers, the tumour microenvironment (TME) plays a critical role in driving anticancer drug resistance. Cancer cells, through their altered metabolic activity, secrete various metabolites that reshape the TME, influencing not only tumour progression but also its sensitivity to treatments.

This interdisciplinary project will combine novel advanced biosensors and imaging techniques with cell and molecular biology methods to elucidate the role that cancer microenvironmental factors play in drug resistance and thus can help in the development of improved anticancer drug therapies.

This is a joint project with Imperial College London and a potential iCASE project.

SUPERVISORY TEAM

• Supervisor: Dr Elena Sviderskaya at City St George’s. Email: [email protected]
• Co-Supervisor: Professor Yuri Korchev at Imperial College London. Email: [email protected]
• Co-Supervisor: Dr Kenneth Laing at City St George’s. Email: [email protected]

Project Key Words

Cancer, cell biology, molecular biology, biosensors

MRC LID Themes

1. Translational and Implementation Research

MRC skills priority – Interdisciplinary skills:

Advanced mammalian cell culture, cell biology and molecular biology methods including cell proliferation, differentiation, senescence and apoptosis assays, immunostaining. Fluorescence and confocal microscopy.

Advanced high-resolution scanning probe microscopy for live cell imaging and use of novel nano-sensors for analysis of tumour samples.

Develop skills in processing and analysing interdisciplinary data.

Presentation of findings at academic meetings and in peer review publications.

Full-time/Part-time Study

• Is this project available for full-time study? Yes
• Is this project available for part-time study? No

Location & Travel

Students funded through MRC LID are expected to work on site at their primary institution, meeting – at the minimum – the institutional research degree regulations and expectations. Students may also be required to travel for conferences (up to 3 over the duration of the studentship), and for any required training (for research degree study). Other travel expectations and opportunities highlighted by the supervisory team are noted below.

Primary location for duration of this research degree: City St George’s, London

Travel requirements for this project: Visits to Imperial College London.

Eligibility/Requirements

Particular prior educational requirements for a student undertaking this project

• Minimum City St George’s institutional eligibility criteria for doctoral study.
• BSc/BA, 2i or above in a science discipline. Preferably also Master’s degree.
• Prior experience in basic laboratory skills is essential.

Other useful information

• Potential Industrial CASE (iCASE) conversion? = Yes

PROJECT IN MORE DETAIL

Rationale and logistics

Melanoma is the cancer with the most rapidly growing incidence in the UK. In melanoma, like in many other cancers, the tumour microenvironment (TME) plays a critical role in driving anticancer drug resistance. Cancer cells, through their altered metabolic activity, secrete various metabolites that reshape the TME, influencing not only tumour progression but also resistance to chemotherapy, targeted therapies, and immunotherapy.

This interdisciplinary project will use novel biosensors to monitor and control cancer microenvironmental factors including extracellular acidity (pH), production of ATP (adenosine triphosphate), hypoxia, lactate concentration, and ROS (reactive oxygen species), to evaluate their involvement in anticancer drug resistance. This novel approach could be applied to other types of cancer and could be transformative in helping to understand the role of the TME in cancer progression and treatment, as well as allowing the development of improved diagnostics and therapies.

Objectives

1. To establish 3R melanoma cell line models, where various TMEs will be controlled by monitoring the local extracellular concentrations of tumour metabolites (eg. pH, ATP, ROS, O2, lactate) and continuously readjusting them to specific TMEs.
2. In melanoma cell line models with various defined TMEs, to evaluate changes in gene expression profiles to anticancer drugs and monitor the cell responses to treatments.
3. To evaluate the effects of anticancer drugs in melanoma cell models representing different stages of progression and various TMEs, focusing on changes in melanoma cell phenotype, pericellular pH, stiffness, intracellular ROS and drug resistance.

Techniques to be used

This project will combine expertise in molecular and cellular biology techniques available in the groups of Dr Sviderskaya and Dr Laing at City St George’s and rich resources of the Functional Genomics Cell Bank at City St George’s of which Dr Sviderskaya is Director together with the physical/engineering approaches available in Professor Korchev’s laboratory at Imperial College London.

We will use non-contact scanning probe microscopy for 3D cell topographical imaging and novel nanoprobes to monitor chemical metabolites in human melanoma cell line models including intracellular ROS, extracellular ATP and oxygen, pH mapping and to perform accurate measurement of cell stiffness and map cell mechanical properties. Melanoma-specific and nonspecific drugs that are often part of a combination therapy and used in other types of cancer will be used in this project.

Availability of any required databases or specialist materials

We confirm availability of the required databases and specialist materials necessary for the project at City St George’s or Imperial College.

The likelihood of success and potential risks to the project

All expertise and techniques that we propose to use are available at City St George’s and Imperial College. We do not foresee any risks to the project.

The lab environment

We pride ourselves on a highly motivated, positive, friendly and supportive laboratory working environment. The collaborative nature of our research means that we share both scientific knowledge and innovative techniques with our collaborators worldwide. Our students thrive at St George’s and Imperial College.

MRC LID LINKS

• To apply for a studentship: MRC LID How to Apply
• For more information about the DTP: MRC LID About Us