LIMR Cancer: Characterization of EGFR signaling activated by the endothelium in the process of breast cancer metastasis to the brain

The Epidermal Growth Factor Receptor (EGFR) is important in normal physiology regulating epithelial development and homeostasis. In cancer, deregulation resulting from mutation, amplification or transcriptional upregulation promotes tumorigenesis. Consequently, EGFR is the target of many cancer therapies approved in clinical practice. Our previous work investigated how EGFR signaling promotes metastasis of breast cancer cells to the brain. Brain metastases are untreatable leading to patient death. We found that the guanine nucleotide exchange factor DOCK4 which activates RAC1 downstream of EGFR is essential for extravasation of triple negative breast cancer cells to the brain in vivo. Critically, we found that EGFR is activated by the brain endothelium. We have also developed a 3-dimensional culture model which allows investigation of the process of cancer cells crossing the endothelium through perfused endothelial tubes. Our aim will be to investigate whether EGFR inhibitors inhibit brain metastasis using the culture and in vivo models available in our laboratory. Furthermore, we will determine how breast cancer dormancy or proliferation in the brain are affected by EGFR inhibition. In addition, we will employ RNA sequencing to identify new druggable targets in the EGFR pathway. The studies will help understand how breast cancer cells spread and may validate EGFR inhibition as strategy to inhibit metastasis and early growth in the brain.

<h5>Techniques associated with this project:</h5> <p>The PhD student will gain experience in state-of-the-art biomedical research methods and techniques including RNA sequencing and pathway analysis, culture of 3-dimensional model, confocal microscopy, immunohistochemistry and immunofluorescence, western blotting, in vitro and in vivo extravasation, and determination of proliferation and dormancy using appropriate reporters.</p> <p>This project is part of the <a href="https://medicinehealth.leeds.ac.uk/leeds-institute-research-st-james/doc/international-phd-academy-medical-research">International PhD Academy: Medical Research</a>.</p> <p><strong>In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.</strong></p>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. You should complete an <a href="https://medicinehealth.leeds.ac.uk/faculty-graduate-school/doc/apply-2">online application form</a> and attach the following documentation to support your application. </p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks (or marks so far if still studying)</li> <li>Evidence that you meet the programme’s minimum English language requirements (if applicable, see requirement below)</li> <li>Evidence of funding to support your studies</li> </ul> <p>To help us identify that you are applying for this project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Medicine, Health & Human Disease as your planned programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> </ul>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. For entry requirements for all other research degrees we offer, please contact us.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

<p>Informal enquires about regarding the bespoke taught first year of the PhD programme and research projects can be made by contacting <a href="mailto:LIMRPhD@leeds.ac.uk">LIMRPhD@leeds.ac.uk</a>.</p> <p>Enquiries regarding the application process should be directed to the Faculty of Medicine and Health Graduate School e: <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p>