Vascular Biology and Cell Trafficking Laboratory
Blood vessels make up the vascular system that transports cells, oxygen and nutrients throughout all tissues and organs. Blood vessels are critical in the fight against disease and improved understanding of endothelial cells (ECs, specialised cells which form the inner lining of blood vessels), will provide new treatment options for many diseases, including cancer, heart disease and diabetes.
Our laboratory has four main areas of interest.
Firstly, vasculogenic mimicry (VM), a process wherein cancer cells themselves form vascular-like structures to increase access to the blood supply to assist in tumour growth. In both breast cancer and melanoma, increased VM is associated with poor clinical outcome. We have begun to identify novel elements in VM and are now targeting these in an attempt to prevent the progression of breast cancer and melanoma.
Secondly, endothelial progenitor cells (EPCs) directly contribute to blood vessel formation (vasculogenesis) and can be used to support organ transplantation. Using nanotechnology we are developing smart surface biomaterials to co-transplant EPCs with insulin-producing beta islet cells to help cure patients with type 1 diabetes.
Third, vascular occlusions are a major contributor to cardiovascular disease (CVD) which is a leading cause of death worldwide. Overcoming these occlusions requires insertion of devices (such as stents) to maintain vessel diameter. Our innovative concept modifies stents (first coated with a patented low-fouling surface and then topped with our novel peptides to specifically capture endothelial cells) to provide rapid revascularisation of implanted devices for minimal intervention and medication.
Finally, blood vessels are intimately involved in the development of allergic inflammation with ECs rapidly recruiting circulating white blood cells (leukocytes) such as neutrophils. As neutrophils contribute to the most severe and difficult to treat allergies, understanding how they are recruited by the vasculature is key to preventing this prevalent and debilitating disease.
Current research projects
- Vasculogenic mimicry in cancer progression: For solid tumours to grow they require access to the blood supply for the provision of oxygen and nutrients. Highly vascularised tumours correlate with poor survival for patients with e.g. melanoma and breast cancer. Tumour vascularisation can occur via a number of processes including angiogenesis (the proliferation of existing blood vessel endothelial cells (ECs), which form the inner monolayer of blood vessels) as well as an EC-independent manner known as vasculogenic mimicry (VM, wherein vascular-like channels are formed by the cancer cells themselves). Our work in melanoma and breast cancer has identified key growth factors and adhesion molecules which underpin VM and are now of interest in terms of developing new treatment opportunities for cancer sufferers.
- Endothelial progenitor cells (EPCs) in disease: With a focus on how the vasculature contributes to health and disease, we have a strong programme on endothelial progenitor cells (the precursors of cells which form the inner lining of all blood vessels).Having recently identified a suite of novel surface expressed proteins by EPCs we are have begun to unravel how EPCs contribute to health and disease. For example, in Type 1 Diabetes, pancreatic islet transplantation is the only current cure, but success is limited by death of insulin producing beta cells post-transplantation. EPCs have the potential to improve islet engraftment and production of insulin. Our work understanding the critical cross-talk between the vasculature and beta islet cells together with smart surface materials will advance our ability to cure diabetes.
- Nanotechnology and biomaterials for cardiovascular disease: Exposure of foreign materials (e.g. metal stents) directly with blood can immediately trigger platelet activations (thrombosis) while restenosis can build up over time as vascular smooth muscle cells (SMCs) migrate to the site of the trauma and accumulate on exposed portions of the device. Despite incremental advances in stents and post operative care, there still exists a large gap between the current best performing stents and what would be considered the ideal performance for these implanted devices. Our novel technology could see a closing of this gap with a new generation of low-fouling implantable medical devices.
- A new target to treat allergy: Rapid recruitment of neutrophils to a site of inflammation is associated with severe and difficult-to-manage allergy. We are currently examining the role of sphingosine kinase (SK) in histamine-induced neutrophil recruitment and how attenuation of this enzyme may be a new treatment option for allergic inflammation.
Rojas-Canales D, Penko D, Myo Min KK, Parham KA, Peiris H, Haberberger RV, Pitson SM, Drogemuller C, Keating DJ, Grey ST, Coates PTH, Bonder CS*, Jessup CJ* Local sphingosine kinase 1 activity improves islet transplantation. Diabetes, 66:1301-1311, 2017. * equal senior authors
Pulford E, Hocking A, Griggs K, McEvoy J, Bonder CS, Henderson DW, Klebe S. Vasculogenic mimicry in malignant mesothelioma: an experimental and immunohistochemical analysis. Pathology, 48(7):650-659, 2016.
Dalilottojari A, Delalat B, Harding FJ, Cockshell MP, Bonder CS and Voelcker NH. Porous silicon based cell microarrays: optimising human endothelial cell-material surface interactions and bioactive release. Biomacromolecules, 17(11):3724-3731, 2016.
Tan LY, Mintoff C, Johan MZ, Ebert BW, Fedele C, Zhang YF, Szeto P, Sheppard KE, McArthur GA, Foster-Smith E, Ruszkiewicz A, Brown MP, Bonder CS*, Shackleton M*, Ebert LM*. Desmoglein 2 promotes vasculogenic mimicry in melanoma and is associated with poor clinical outcome. Oncotarget, 2016 Jun 22. doi: 10.18632/oncotarget.10216. [Epub]. * equal senior authors.
Ebert LM, Tan LY, Johan MZ, Myo Min KK, Cockshell MP, Parham KA, Betterman K, Szeto P, Boyle S, Silva L, Peng A, Zhang Y, Ruszkiewicz A, Zannettino ACW, Gronthos S, Koblar S, Harvey NL, Lopez AF, Shackleton M, Bonder CS. A non-canonical role for desmoglein-2 in endothelial cells: implications for neoangiogenesis. Angiogenesis, 19(4):463-86, 2016.
Sun WY, Dimasi DA, Pitman MR, Zhuang YZ, Heddle R, Pitson SM, Grimbaldeston MA, Bonder CS. Topical application of Fingolimod perturbs cutaneous inflammation. Journal of Immunology, 196(9):3854-3864, 2016.
Dimasi DA, Pitson SM, Bonder CS. Examining the role of sphingosine kinase-2 in the regulation of endothelial cell barrier integrity. Microcirculation, 23(3):248-65, 2016
Harper RL, Reynolds AM, Bonder CS, Reynolds PN. BMPR2 Gene Therapy for PAH acts via Smad and non-Smad signalling Respirology, 21(4):727-33, 2016.
Etemadi N, Chopin M, Rickard JA, Tanzer MC, Abeysekera W, Anderton H, Hall C, Spall S, Wang B, Pitson SM, Bonder CS, Hla T, Alexander WS,Wong W, Smyth G, Vaux DL, Nutt SL, Nachbur U, Ernset M, Silke J.TRAF2 regulates TNF and NF-κB signalling to suppress apoptosis and skin inflammation independently of Sphingosine Kinase-1. eLife, pii: e10592. doi: 10.7554/eLife.10592. 2015.
Parham K, Zebol J, Tooley K, Sun WY, Moldenhauer L, Cockshell M, Gliddon B, Moretti P, Tigyi G, Pitson S, Bonder CS.Sphingosine 1-phosphate is a ligand for PPARg which regulates neoangiogenesis. FASEB J, 29(9):3638-5, 2015.
Moldenhauer L, Cockshell M, Frost L, Parham K, Tvorogov D, Tan LY, Ebert L, Tooley K, Worthley S, Lopez AF, Bonder CS.Interleukin-3 greatly expands non-adherent endothelial forming cells with pro-angiogenic properties. Stem Cell Research, 14(3):380-395, 2015.
Pitman MR, Powell JA, Coolen C, Moretti PAB, Pham DH, Ebert LM, Bonder CS, Gliddon BL, Pitson SM. An ATP-competitive sphingosine kinase inhibitor revealed from structural model-based virtual screening demonstrates anti-cancer properties. Oncotarget, 6(9):7065-83, 2015.
Penko D, Rojas-Canales D, Peiris H, Sun WY, Drogemuller C, Coates PTH, Bonder CS, Jessup CJ. Endothelial progenitor cells enhance islet engraftment, influence beta cell function and modulate connexin 36 expression. Cell Transplantation, 24(1):37-48, 2015.
Sun WY, Abeynaike DL, Escarbe S, Smith CD, Pitson SM, Hickey MJ and Bonder CS. Rapid histamine-induced neutrophil recruitment is sphingosine kinase-1 dependent. Am J Pathol, 180(4):1740-50, 2012.
Appleby S, Cockshell M, Pippal J, Thompson E, Barrett J, Tooley K, Sen S, Sun W, Grose R, Nicholson I, Levina V, Cooke I, Talbo G, Lopez A and Bonder CS.Characterization of a distinct population of human endothelial forming cells and their recruitment via intercellular adhesion molecule-3. PloS ONE, 7(11): e46996, 2012.
Sun WY., Pitson SM and Bonder CS. Tumour necrosis factor induced neutrophil adhesion occurs via a sphingosine kinase-1 dependent activation of endothelial a5b1 integrin. Am J Pathology. 177(1):436-46, 2010.
Bonder CS, Sun WY, Matthews T, Cassano C, Li X, Ramshaw HS, Pitson SM, Lopez AF, Coates PT, Prioa R, Vadas MA and Gamble JR. Sphingosine kinase regulates the rate of endothelial progenitor cell differentiation. Blood 113(9):2108-17, 2009.
Gamble JR, Sun WY, Li X, Hahn C, Pitson SM, Vadas MA and Bonder CS. Sphingosine kinase associates with integrin avb3 to promote endothelial cell survival. Am J Pathology. 175(5):2217-25, 2009.