Background and problem:
HER2 is a protein that is overexpressed in 20-25% of invasive breast cancer. The monoclonal antibody, Herceptin (trastuzumab) targets HER2 and is considered one of the most effective treatments in oncology. However, many cancer patients do not benefit from Herceptin treatment despite having HER2-positive tumours; whilst others acquire resistance after a period of time. Understanding why these patients are resistant will ensure effective treatment options are used to maximise drug utility, effectiveness and clinical outcomes, particularly as Herceptin-based treatments are now being cross-purposed to several different solid tumour types. Syndecan-1 (SDC1) is a proteoglycan displayed at the cell surface where it modulates many receptor functions, including HER2 (1). Herceptin has also been shown to interact with proteoglycans and changes in tumour proteoglycan glycosylation have been shown to affect the efficacy of Herceptin (2). In this project, we wish to create a library of different SDC1 forms to identify which interact with Herceptin and HER2. Using a mixture of wet lab techniques (eg. SDS-PAGE, cell culture, CRISPR-Cas) we will explore which part(s) of SDC1 binds Herceptin and how this affects treatment resistance. Understanding the mechanism of binding will inspire new therapeutics and guide precision medicine for cancer patients.
Aims and Method(s):
The project will use a combination of dry- and wet-lab based research to investigate the following aims:
- Aim 1: To develop specific protein variants of SDC1 using CRISPR-CAS gene editing
- Aim 2: To investigate the impact of SDC1 structure on its interaction with HER2 and Herceptin
- Wet lab techniques may include: CRISPR-Cas editing, cell culture, cell motility assays, SDS-PAGE, Western blotting, and Differential Scanning Fluorimetry (DSF).
Contact person(s):
- Dr. Marissa Maciej-Hulme (Faculty of Health Sciences, OsloMet) marissa.maciej-hulme@oslomet.no
- Prof. Kristian Prydz (Department of Biosciences, UiO) kristian.prydz@ibv.uio.no
References:
- Wang H, Jin H, Rapraeger AC. Syndecan-1 and Syndecan-4 Capture Epidermal Growth Factor Receptor Family Members and the α3β1 Integrin Via Binding Sites in Their Ectodomains. J Biol Chem. 2015 Oct;290(43):26103–13.
- Suarez ER, Paredes-Gamero EJ, Del Giglio A, Dos Santos Tersariol IL, Nader HB, Pinhal MAS. Heparan sulfate mediates trastuzumab effect in breast cancer cells. BMC Cancer. 2013 Dec;13(1):444.