ABC transporters: a unifying force in tumour invasion and drug resistance?
Lead Research Organisation:
University of Nottingham
Department Name: School of Medicine
Abstract
The supervisors have a long-standing interest in the molecular basis of two of the hallmarks of cancer; namely the ability to evade therapy, and the ability to migrate through surrounding tissue (metastasis/invasion). We have evidence that implicates a multidrug ATP binding cassette transporter B1 (ABCB1/P-glycoprotein) in both of these processes. This is a remarkable observation because until now ABCB1 has been thought of purely as a non-specific efflux pump that protects cells from toxic compounds. The major focus of this project will be to unravel the molecular mechanisms that enable ABCB1 to be pivotal in both these processes; for example, how is ABCB1s involvement in cell migration regulated? Is it a transporter for a chemical signal that normally inhibits cell migration? Is it exporting a signal that makes the tumour microenvironment more susceptible to invasion?
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M008770/1 | 01/10/2015 | 31/10/2024 | |||
| 1796047 | Studentship | BB/M008770/1 | 01/10/2016 | 28/02/2021 |
| Description | TWIST1 is a transcription factor that is involved in the metastatic process in many different types of cancer. I have revealed that TWIST1 is able to bind to ABCB1 (the multi-drug transporter) and therefore could regulate it. I have also shown that high TWIST1 levels correlate to metastasis in medulloblastoma tumour patient samples. This finding has made me further investigate the role of TWIST1 in the metastatic process to see how the transcription factor works and what else it could be regulating. To do this I have used a migration and invasion model to see if inhibiting TWIST1 could prevent cell migration in a metastatic cell line. I inhibited TWIST1 with a drug called harmine. I found that the drug degraded TWIST1 which resulted in less cells being able to migrate in the model. In addition I also inhibited ABCB1 and TWIST1 and found that cell migration decreased even further. Interestingly when TWIST1 was inhibited the levels of ABCB1 decreased. All of this data suggests that TWIST1 and ABCB1 are involved in the metastatic process and TWIST1 is controlling ABCB1. I have also sent samples off to be sequenced to see what else TWISt1 is regulating in metastatic cells. |
| Exploitation Route | Novel inhibitors could be developed to target both TWIST1 and ABCB1 to overcome both drug resistance and metastasis in medulloblastoma patients. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | UNICAS |
| Amount | £4,969 (GBP) |
| Organisation | University of Nottingham |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 04/2019 |
| End | 07/2019 |
| Description | International Symposium of Paediatric Neuro-Oncologoy (ISPNO) |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | I attended the ISPNO conference where I presented my research in the form of a scientific poster. The poster was available for everyone who attended the conference to have a look at and as me questions. I had a lot of interest from a range of people over the world who asked me questions about my project and also gave me feedback on new techniques/ ideas I could look in to. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Wonder 2017 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | The event is a fair held at The University of Nottingham which is aimed at the general public, in particular younger children. The stand that we had was to try and make children more interested in science but to also to educate both parents and children of the side effects of medulloblastomas. This lead onto a lot of parents interested and asking questions about the side effects and how this could impact children. |
| Year(s) Of Engagement Activity | 2017 |