Targeting the activated stroma to limit breast cancer metastasis

Most sold tumours are characterised by a significant infiltration of fibroblasts and a proportion of these will acquire an activated cancer-associated fibroblast (CAF) phenotype. There is now extensive evidence functionally implicating CAFs in tumour progression and metastasis via their ability to deposit and remodel the extracellular matrix, secrete pro-tumourigenic factors.

This project will initially focus on the Endo180 receptor. Our laboratory has demonstrated that Endo180 (also known as MRC2, CD280, uPARAP) is predominantly expressed by CAFs in the tumour microenvironment (with lower level expression in normal tissue fibroblasts), where it functions as a promigratory, novel collagen update receptor. Using mice with a genetic deletion in Endo180, we have shown that End180 is not required for normal tissue homeostasis but its absence significantly impairs both primary breast cancer tumour growth and metastatic colonisation of the lung, liver and bones. These data provide pre-clinical evidence that targeting Endo180 may server to limit the pro-tumourigenic features of the tumour/metastatic microenvironment with limited toxicity to normal tissues.
The goal in this project is to use our existing anti-Endo180 monoclonal antibodies to generated novel antibody based therapeutics to target Endo180 expressing fibroblasts. In collaboration with colleagues at King's College London the student will be involved in developed Fc-modified antibodies and antibody drug conjugates. The student will test the efficacy of these reagents in 3D tumour-fibroblast co-culture models and in in vivo metastasis models, and address any issue of unwanted toxicities. In addition, the student will further explore the role of CAF activation at metastatic sites. In particular, the student will address the functional properties associated with the Endo180-positive CAF subset and the consequences of targeting this population on other fibroblast subsets.

This is an exciting project addressing a critical issue in cancer research - 'Identifying therapeutic strategies for targeting the stroma to constrain breast cancer metastatic relapse'. The project will integrate closely with other projects in the laboratory to inform more broadly our understanding of how to limit the development and spread of metastatic disease.

Download a PDF of the complete project proposal: https://d1ijoxngr27nfi.cloudfront.net/docs/default-source/studying-at-the-icr/1_isacke_swain_icr-studentship.pdf?sfvrsn=5beb5e69_2

Candidate profile
Candidates must have a first class or upper second class honours BSc Honours in biological sciences, Biological chemistry or other relevant degree subjects

How to apply
Full details about these studentship projects, and the online application form, are available on our website, at: www.icr.ac.uk/phds Applications for all projects should be made online. Please ensure that you read and follow the application instructions very carefully.

Closing date: Monday 19th November 2018
Applicants should be available for interview 28h and 29th January 2019.

Please apply via the ICR vacancies web portal
https://apply.icr.ac.uk/