This is what keeps us busy

Research line 1

Molecular regulation of angiogenesis

One of our lines of research investigates the molecular mechanisms that regulate the pathophysiology of angiogenesis. We are very interested in identifying key regulators of angiogenesis that can be used to design new therapeutic interventions to treat diseases occurring with abnormal blood vessels formation. In this sense, work in our laboratory has shown a novel role for the Plasma Membrane Calcium ATPase proteins as a negative regulator of angiogenesis (Baggott et al, Arterioscler Thromb Vasc Biol. (2014) 34(10):2310-20). Furthermore, we have seen that blockage of PMCA4 function with the small molecule Auryntricarboxilic acid enhances reperfusion of ischeamic limbs in pre-clinical models of critical limb ischaemia (Kurusamy et al, J Mol Cell Cardiol. (2017)109:38-47).

Recent Selected publications on our projects about angiogenesis:

Njegic A, Swiderska A, Marris C, Armesilla AL, Cartwright EJ. Plasma membrane calcium ATPase 1 regulates human umbilical vein endothelial cell angiogenesis and viability. J Mol Cell Cardiol 2021 Mar 27;156:79-81. https://doi.org/10.1016/j.yjmcc.2021.03.011
Savage AM, Kurusamy S, Chen Y, Jiang Z, Chhabria K, MacDonald RB, Kim HR, Wilson HL, van Eeden FJM, Armesilla AL, Chico TJA, Wilkinson RN. Tmem33 is essential for VEGF-mediated endothelial calcium oscillations and angiogenesis. Nat Commun. 2019 Feb 13;10(1):732. https://doi.org/10.1038/s41467-019-08590-7
Kurusamy S, López-Maderuelo D, Little R, Cadagan D, Savage AM, Ihugba JC, Baggott RR, Rowther FB, Martínez-Martínez S, Arco PG, Murcott C, Wang W, Francisco Nistal J, Oceandy D, Neyses L, Wilkinson RN, Cartwright EJ, Redondo JM, Armesilla AL. Selective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusion. J Mol Cell Cardiol. 2017 Aug;109:38-47. https://doi.org/10.1016/j.yjmcc.2017.07.001
Baggott RR, Alfranca A, López-Maderuelo D, Mohamed TM, Escolano A, Oller J, Ornes BC, Kurusamy S, Rowther FB, Brown JE, Oceandy D, Cartwright EJ, Wang W, Gómez-del Arco P, Martínez-Martínez S, Neyses L, Redondo JM, Armesilla AL.Plasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through interaction with calcineurin. Arterioscler Thromb Vasc Biol (2014) Oct;34(10):2310-20. https://doi.org/10.1161/atvbaha.114.304363

Research Line 2

Molecular mechanisms deregulated in cardiovascular disease

Cardiovascular disease (CVD) encompasses a number of different conditions including coronary heart disease, stroke, and peripheral vascular disease. CVD currently represents a major cause of death, morbidity, and economic burden all around the world, accounting for more than 17 million deaths each year. In the UK, more than a quarter of all deaths are caused by CVD; that is more than 160,000 deaths each year – or one death every three minutes.

Our group is characterising the molecular mechanisms deregulated in diseased arteries during the onset and progression of atherosclerosis, aneurysm, or pulmonary arterial hypertension. These studies will reveal new molecular targets that will be used to design more efficient therapeutic strategies to treat patients suffering from CVD.

Another avenue that we are exploring in the lab is to characterise the effects of aberrant expression of microRNAs in endothelial cells during cardiovascular disease. We are specially interested in studying the consequences of ectopic expression of "cardiac" microRNAs in endothelial cells during pathological settings. The characterisation of the target genes affected by aberrant expression of these microRNAs in endothelial cells will shed new insights into the molecular processes deregulated during endothelial dysfunction.

Recent Selected publications on our projects about this line of research:

Martínez-Martínez S, Lozano-Vidal N, López-Maderuelo MD, Jiménez-Borreguero LJ, Armesilla AL, Redondo JM. Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice. FEBS J 2019 Jan;286(1):46-65. https://doi.org/10.1111/febs.14718
Oller J, Alfranca A, Méndez-Barbero N, Villahoz S, Lozano-Vidal N, Martín-Alonso M, Arroyo AG, Escolano A, Armesilla AL, Campanero MR, Redondo JM. C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling. Mol Cell Biol 2015 Oct;35(19):3409-22. https://doi.org/10.1128/mcb.00494-15

Research Line 3

Evasion of anti-VEGF treatment by brain tumors

Glioblastoma also known as glioblastoma multiform (GBM) is the most common primary malignant tumour of the brain affecting the elderly, with a rising incidence in the UK. At present there is no cure for patients suffering from GBM.
These tumours are characterised by the abundance of microvascular proliferation and invasive glioma cells, which accounts for its poor prognosis. In humans, vascular endothelial growth factor-A (VEGF-A) has been implicated in GBM vascularisation. VEGF-A antagonists are being used in clinic to treat GBM. However, the effect of these agents is short-lived, with limited impact on overall survival. After a brief period of huge tumor reduction, the tumoral cells acquire new mechanisms to evade the treatment and patients suffer tumour revascularisation, and a significant increase in tumour growth and invasiveness.
As a first step towards understanding the molecular mechanisms implicated in anti-VEGF evasion, we are using primary human cells isolated from brain tumor patients that are treat in the laboratory with anti-VEGF drugs. We are determining the molecular changes induced in these cells by these drugs to disclose the mechanisms implicated in tumor evasion of anti-VEGF drugs.

Recent Selected publications on our studies on cancer:

Butcher K, Kannappan V, Kilari RS, Morris MR, McConville C, Armesilla AL, Wang W. Investigation of the key chemical structures involved in the anticancer activity of disulfiram in A549 non-small cell lung cancer cell line. BMC Cancer 2018 Jul 21;18(1):753. https://doi.org/10.1186/s12885-018-4617-x
Liu P, Wang Z, Brown S, Kannappan V, Tawari PE, Jiang W, Irache JM, Tang JZ, Armesilla AL, Darling JL, Tang X, Wang W. Liposome encapsulated Disulfiram inhibits NFκB pathway and targets breast cancer stem cells in vitro and in vivo. Oncotarget 2014 Sep 15;5(17):7471-85. https://doi.org/10.18632/oncotarget.2166
Liu P, Brown S, Goktug T, Channathodiyil P, Kannappan V, Hugnot JP, Guichet PO, Bian X, Armesilla AL, Darling JL, Wang W. Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells. Br J Cancer 2012 Oct 23;107(9):1488-97. https://doi.org/10.1038/bjc.2012.442
Baggott RR, Mohamed TM, Oceandy D, Holton M, Blanc MC, Roux-Soro SC, Brown S, Brown JE, Cartwright EJ, Wang W, Neyses L, Armesilla AL. Disruption of the interaction between PMCA2 and calcineurin triggers apoptosis and enhances paclitaxel-induced cytotoxicity in breast cancer cells. Carcinogenesis 2012 Dec;33(12):2362-8. https://doi.org/10.1093/carcin/bgs282