Signal Transduction and Tumour Microenvironment Group
- Dr Georgia Mavria: Group Leader
- Dr Chiara Galloni: Postdoctoral Research Fellow
- Mr Teklu Egnuni: PhD student
- Ms Leander Stewart: PhD student
- Ms Carla Oliveira: MSc student
- Ms Anastasia Widyadari: PhD student
The aggressive nature of brain tumours and resistance to standard and targeted therapies can be attributed to intrinsic genetic mutations and stem-like origins. The molecular pathways activated by mutations, and cellular stemness are highly influenced by the brain tumour microenvironment. Our work is focused on elucidating signaling pathways driven by the microenvironment that promote tumour progression, and understanding the contribution of specific niches and their unique cellular and biophysical properties to tumour resistance to therapy and recurrence.
We use a range of cellular assays, imaging techniques, genetic deletion approaches and mouse models of human cancer to investigate biological function, combined with state-of-the-art mass spectrometry and biochemical techniques to understand the molecular basis of protein: protein interactions in the signaling pathways we investigate. Our overarching goal is to characterize and validate new targets, and interactions that can be targeted therapeutically in glioblastoma, and breast cancer brain metastases.
Glioblastoma stem cell – host interactions in the brain microenvironment
Starting with analysis of patient material from primary tumours and their recurrences, and using relevant in vivo models, we are investigating the origin and function of supporting cellular components within the tumour microenvironment, and their impact on the behavior of glioblastoma stem cells. The brain tumour perivascular niche provides a protective environment for glioblastoma stem cells promoting resistance to current treatments, while blood vessels also provide permissive routes along which cancer cell invasion takes place. We are working to identify the molecular basis of glioblastoma stem cell- endothelial interactions, understand how aberrant vascular morphologies and function arise in GBM, and how they can be normalized to improve radiotherapy and chemotherapy. Concurrently, we are developing 3D models that recapitulate characteristics of patient tumours, to aid us with discovery of molecular components that mediate key tumour–host interactions.
Collaborators: Dr Susan Short, Dr Heiko Wurdak, Dr Lucy Stead.
Signalling pathways activated in angiogenesis, metastasis and invasion
Tumour blood vessel abnormality and aberrant function arises at least partly from uncontrolled blood vessel growth and irregular morphology, leading to blood vessel dysfunction. The Rho family of small GTPases are key regulators of cytoskeletal rearrangements and changes in cell shape during blood vessel growth. Activation of Rho GTPases is controlled by positive regulators, guanine nucleotide exchange factors (GEFs) which catalyse the exchange of GDP for GTP; and negative regulators, GTPase activating proteins (GAPs) which accelerate the intrinsic GTPase activity. Recent work in our laboratory has delineated a new unappreciated signaling module comprising the Rac GEF DOCK4, upstream regulators and downstream effectors, that control sprouting and blood vessel lumen size [Abraham et al. Nat Communs 2015]. We are investigating the effects of blocking the endothelial RhoG-DOCK4-Rac-DOCK9-Cdc42 signalling in blood vessel normalization in glioblastoma, and inhibiting DOCK4 in breast cancer brain metastasis.
Malignant Gliomas are some of the most invasive tumours. Given the large number of molecular drivers and mutations associated with the disease, targeting downstream signaling pathways may provide a better means of interfering with invasion. To this end we are working to block Rac1 activation by targeting DOCK4 and other regulators.
In collaboration with Dr Mihaela Lorger’s group we are investigating the role of DOCK4 in the extravasation of breast cancer cells to the brain. Funded by Breast Cancer Now.
Responses to insufficient oxygen supply are important both in tumour biology and cardiovascular disease. Funded by the British Heart Foundation.
For our research on vascular physiology and ischemia see http://www.cardiovascular.leeds.ac.uk/investigators/endothelial.php
Targeting Rho GEF interactions
In collaboration with the Leeds Astbury centre for structural biology we are investigating the interaction of the Rac GEF DOCK4 with Cdc42 GEF DOCK9 (Abraham et al. Nat Commun. 2015) and the molecular basis of DOCK4 autoinhibition. We know that the SH3 domain of DOCK4 is required for the interaction and we are currently working to identify what DOCK9 domains are required for interaction. We are using a combination of classical mutagenesis of PxxP sites within the DOCK9 protein sequence, and peptide array analyses to systematically screen for the necessary DOCK9 domains. Ultimately, these studies will allow us to elucidate the molecular basis of the interaction, and aided by structural data initiate a chemical inhibitor screening program. Such inhibitors will be used as tools to further understand the biology of this signaling system, and can provide lead compounds for future development of therapeutics.
Collaborators: Prof Richard Bayliss (Astbury Centre for Structural Biology), Prof Alexander Breeze (Astbury Centre for Structural Biology), Prof John Ladbury (Faculty of Biological Sciences), Dr Nathanael Gray (Dana Farber Institute for Cancer Research).
Publications and Abstracts
Grant, M., Grant, G. and Mavria, G. (2016). Assessing the components of a novel VEGF signalling cascade as potential prognostic markers in glioblastoma (P5. 253). Neurology 86(suppl 16), P5-253.
Abraham S, Scarcia M, Bagshaw RD, McMahon K, Grant G, Harvey T, Yeo M, Esteves FO, Thygesen HH, Jones PF, Speirs V, Hanby AM, Selby PJ, Lorger M, Dear TN, Pawson T, Marshall CJ and Mavria G (2015). A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis Nat Commun. 6, 7286.
Nash C, Mavria G, Baxter E, Holliday D, Treanor D, Tomlinson D, Novistkaya V, Hanby A, Berditchevski F, Speirs V. (2015). Development and characterisation of a 3D multi-cellular in vitro model of normal human breast: a tool for cancer initiation studies. Oncotarget 6, 13731-41.
Kaur S, Leszczynska K, Abraham S, Scarcia M, Hiltbrunner S, Marshall CJ, Mavria G, Bicknell R, Heath VL (2011). RhoJ/TCL regulates endothelial motility and tube formation and modulates actomyosin contractility and focal adhesion numbers Arterioscler Thromb Vasc Biol. 31, 657-64.
Hetheridge C, Mavria G*, Mellor H. (2011). Uses of the in vitro endothelial-fibroblast organotypic co-culture assay in angiogenesis research. Biochem Soc Trans. 39, 1597-600.
Abraham S, Yeo M, Montero-Balaguer M, Paterson H, Dejana E, Marshall CJ, Mavria G (2009).VE-cadherin suppresses sprouting via signalling to MLC2 phosphorylation Curr Biol. 19, 668-74.
Mavria G, Abraham S, Yeo M and Marshall CJ (2008). Role of MAP-kinase, RhoGTPases and actomyosin contractility in endothelial cell migration and vessel establishment. FASEB Journal 22, 611.
Mavria G*, Vercoulen Y, Yeo M, Paterson H, Karasarides M, Marais R, Bird D, Marshall CJ* (2006).ERK-MAPK signalling opposes Rho-kinase to promote endothelial cell survival and sprouting during angiogenesis Cancer Cell. 9, 33-44.
Gonzalez-Garcia A, Pritchard CA, Paterson HF, Mavria G, Stamp G, Marshall CJ (2005)
RalGDS is required for tumour formation in a model of skin carcinogenesis. Cancer Cell. 7, 219-26.
Croft DR, Sahai E, Mavria G, Li S, Tsai J, Lee W, Marshall CJ, Olson MF (2004)
Conditional ROCK activation in vivo induces tumor cell dissemination and angiogenesis Cancer Res. 64, 8994-9001.