Enhancing radiotherapy sensitisation and improving cancer control by modulating tumour microenvironment derived angiocrine signalling
Prof K Hodivala-Dilke
Dr S Boulton
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
Radiotherapy resistance constitutes a major limitation for effective cancer treatment, emphasising the need to understand the mechanism(s) of radiotherapy sensitisation. Recent studies have identified new mechanisms whereby radiosensitisation is controlled by the tumour microenvironment.
Lung cancer is the most common cause of cancer death in the UK and non-small cell lung cancer (NSCLC) radiotherapy is part of the standard of care for patients with advanced disease. Despite this, 5-year survival is only 32%.
We published that factors made by tumour blood vessel-lining endothelial cells, control radiosensitivity in the tumour cell compartment . Specifically, endothelial cells exposed to radiation change their production of secreted factors. These blood vessel-derived, angiocrine, factors protect the surrounding neoplastic cells causing the tumour to become resistant to radiotherapy. Our laboratory has established precise functions for cell surface receptors and their common downstream target, FAK, in the tumour stroma, showing that differential expression of these molecules in stromal cells modifies cancer behaviour [2, 3]. We have also discovered that deletion of endothelial-cell focal adhesion kinase (FAK), in established lung tumours, does not affect tumour angiogenesis or drug delivery, but enhances radiosensitisation by reducing cytokine production . This fundamental finding suggests a radical new strategy with potential to improve tumour cell radiosensitisation, not by targeting the tumour cells themselves, but by targeting the blood vessels to modulate their angiocrine profiles.
The proposed multidisciplinary PhD project will combine in vivo and in vitro techniques already established in our laboratory to identify the molecular mechanisms that underlie the angiocrine control of radiosensitisation with the ultimate aim to develop novel strategies to improve radiotherapy efficacy. This project bridges expertise across London in tumour microenvironment research with radiotherapy and DNA damage control providing exciting insights into radiotherapy control.
1.Identify the angiocrine signature that regulates radiosensitivity. Using state-of-the-art mouse transgenic technology with unbias metabolomics and phosphoproteomics analysis, this project will identify the radiation-induced primary lung tumour endothelial cell derived angiocrine signature in vivo controlled by endothelial FAK, and compare this with corresponding changes in lung malignant cells.
2.Determine the molecular mechanism underlying angiocrine regulation of radiosensitivity. The mode of action of FAK-regulated DNA-damage and repair in radiation exposed endothelial cells and in tumour cells will be determined under close supervision from international experts at the Crick Institute [4,5]. Subsequent functional validation of these pathways will be carried out in vitro and in vivo using CRISPR-Cas 9 targeting.
3.Develop endothelial-specific targeting agents to combine with, and improve, radiotherapy efficacy. Endothelial cell-specific targeting agents will be developed and finally tested in combination with radiation resistant in vivo cancer models, with the ultimate aim of generating strategies that may translate to clinically relevant methods to improve radiotherapy and overcome resistance.
The successful candidate should have experience in cancer cell biology and a BSc in a relevant subject. For further details on how to apply please visit the CRUK CoL Centre RadNet studentships page: https://www.colcc.ac.uk/radnet-training-programme/
Potential research placements
1.Hodivala-Dilke lab, Barts Cancer Institute. Learn about vascular endothelial cell biology, grow endothelial cells in 3D models relevant to the PhD project and become skilled in angiocrine signalling techniques. Obtain Home Office personal licence.
2.Boulton Lab, Francis Crick Institute. Learn about the mechanisms of DNA damage and DNA damage repair after radiation in endothelial cells and tumour cells. Develop a deeper understanding of the clinical application of radiotherapy in human NSCL (Crispin Hiley).
3.Cutillas and Bianchi labs, Barts Cancer Institute. Basic bioinformatics training, phosphoproteomics and metabolomics.
Due to funding restrictions only UK / EU candidates are eligible to apply
1.Tavora B et al. Endothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy. Nature. 2014 Oct 2;514(7520):112-6.
2.Reynolds A.R. et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors Nat Med. 2009 Apr;15(4):392-400
3.Wong P.P. et al., Dual-action combination therapy enhances angiogenesis while reducing tumor growth and spread. Cancer Cell. 2015 Jan 12;27(1):123-37
4.Sarek G, et al., CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle. Nature. 2019 Nov;575(7783):523-527
5.Hudson A, et al. Is heterogeneity in stage 3 non-small cell lung cancer obscuring the potential benefits of dose-escalated concurrent chemo-radiotherapy in clinical trials? Lung Cancer. 2018 Apr;118:139-147