Staff Profile

I joined the Fibrosis research group in September 2014 to complete my PhD with Professor Fiona Oakley. During my PhD I aimed to uncover the cell specific role of the NF-kB subunit c-Rel in tissue repair, fibrosis and cancer utilising several cell specific knockout mice as well as a novel preclinical human precision cut tissue slice system. I identified c-Rel as a critical regulator of metabolic reprogramming during epithelial dedifferentiation and macrophage polarization and that targeting c-Rel therapeutically in murine and human models of fibrosis in multiple organs was protective.

Following completion of my PhD in Sept 2017, I was awarded a Newcastle University Academic Development Scholarship which allowed me to continue my work in the Fibrosis Research Group and finalise my work ready for publication.

In January 2018, I commenced a joint Research Associate position between the Beatson Institute for Cancer Research in Glasgow and Newcastle University aiming to define the role of neutrophils in liver cancer.

Neutrophils are the most abundant immune cell accounting for roughly 60% of all white blood cells in the circulation. It was typically thought that neutrophils were short lived during the inflammatory response, functioning only as pathogen killers. However, it is now appreciated that neutrophils are much longer lived than first thought and are plastic cells that exist on a spectrum of activation and are critical for shaping the immune response. Much of our current understanding of neutrophil plasticity has been identified in models of cancer. Two neutrophil subsets have been identified in cancer; pro- and anti- inflammatory neutrophils termed N1 and N2 respectively.

Our current CRUK funded research aims to investigate the mechanistic basis for the pro-tumour role of neutrophils in liver cancer with the aim to find novel therapies that modulate neutrophil phenotype and the tumour microenvironment to increase the effectiveness of current immunotherapies.

We employ complex genetically engineered mice and multiple dietary and inducible models of liver cancer and multi-omics approaches to dissect the contribution of neutrophils to liver cancer development. As a result of our investigations and the preclinical data generated, we have identified a novel small molecule inhibitor of neutrophil infiltration that in combination with a approved immunotherapy improves therapy response. As a direct result of this we have recently been awarded a CRUK clinical trial award to perform a phase I/IIb clinical trial in liver cancer.

• Malehmir M, Pfister D, Gallage S, Szydlowska M, Inverso D, Kotsiliti E, Leone V, Peiseler M, Surewaard BGJ, Rath D, Ali A, Wolf MJ, Drescher H, Healy ME, Dauch D, Kroy D, Krenkel O, Kohlhepp M, Engleitner T, Olkus A, Sijmonsma T, Volz J, Deppermann C, Stegner D, Helbling P, Nombela-Arrieta C, Rafiei A, Hinterleitner M, Rall M, Baku F, Borst O, Wilson CL, Leslie J, O'Connor T, Weston CJ, Chauhan A, Adams DH, Sheriff L, Teijeiro A, Prinz M, Bogeska R, Anstee N, Bongers MN, Notohamiprodjo M, Geisler T, Withers DJ, Ware J, Mann DA, Augustin HG, Vegiopoulos A, Milsom MD, Rose AJ, Lalor PF, Llovet JM, Pinyol R, Tacke F, Rad R, Matter M, Djouder N, Kubes P, Knolle PA, Unger K, Zender L, Nieswandt B, Gawaz M, Weber A, Heikenwalder M. Author Correction: Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer (Nature Medicine, (2019), 25, 4, (641-655), 10.1038/s41591-019-0379-5). Nature Medicine 2022, 28, 600.
• Leslie J, Mackey JBG, Jamieson T, Ramon-Gil E, Drake TM, Fercoq F, Clark W, Gilroy K, Hedley A, Nixon C, Luli S, Laszczewska M, Pinyol R, Esteban-Fabro R, Willoughby CE, Haber PK, Andreu-Oller C, Rahbari M, Fan C, Pfister D, Raman S, Wilson N, Muller M, Collins A, Geh D, Fuller A, Mcdonald D, Hulme G, Filby A, Cortes-Lavaud X, Mohamed N-E, Ford CA, Raffo Iraolagoitia XL, Mcfarlane AJ, Mccain MV, Ridgway RA, Roberts EW, Barry ST, Graham GJ, Heikenwalder M, Reeves HL, Llovet JM, Carlin LM, Bird TG, Sansom OJ, Mann DA. CXCR2 inhibition enables NASH-HCC immunotherapy. Gut 2022, 71(10), 2093-2106.
• Geh D, Leslie J, Rumney R, Reeves HL, Bird TG, Mann DA. Neutrophils as potential therapeutic targets in hepatocellular carcinoma. Nature Reviews Gastroenterology and Hepatology 2022.
• Garcia-Macia M, Santos-Ledo A, Leslie J, Paish HL, Collins AL, Scott RS, Watson A, Burgoyne RA, White S, French J, Hammond J, Borthwick LA, Mann J, Bolanos JP, Korolchuk VI, Oakley F, Mann DA. A Mammalian Target of Rapamycin-Perilipin 3 (mTORC1-Plin3) Pathway is essential to Activate Lipophagy and Protects Against Hepatosteatosis. Hepatology 2021, 74(6), 3441-3459.
• Hall Z, Chiarugi D, Charidemou E, Leslie J, Scott E, Pelligrinet L, Allison M, Mocciaro G, Anstee QM, Evan GI, Hoare M, VidalPuig A, Oakley F, Vacca M, Griffin JL. Lipid remodelling in hepatocyte proliferation and hepatocellular carcinoma . Hepatology 2021, 73(3), 1028-1044.
• Lagnado A, Leslie J, Ruchaud-Sparagano MH, Victorelli S, Hirsova P, Ogrodnik M, Collins AL, Grazia Vizioli M, Habiballa L, Saretzki G, Evans SA, Salmonowicz H, Hruby A, Geh D, Pavelko KD, Dolan D, Reeves HL, Grellscheid S, Wilson CH, Pandanaboyana S, Doolittle M, Von Zglinicki T, Oakley F, Gallage S, Wilson CL, Birch J, Carroll B, Chapman J, Heikenwalder M, Neretti N, Khosla S, Masuda CA, Tchkonia T, Kirkland JL, Jurk D, Mann DA, Passos JF. Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner. The EMBO Journal 2021, 40(9), e106048.
• Leslie J, Robinson SM, Oakley F, Luli S. Non-invasive synchronous monitoring of neutrophil migration using whole body near-infrared fluorescence-based imaging. Scientific Reports 2021, 11, 1415.
• Smith ALM, Whitehall JC, Bradshaw C, Gay D, Robertson F, Blain AP, Hudson G, Pyle A, Houghton D, Hunt M, Sampson JN, Stamp C, Mallett G, Amarnath S, Leslie J, Oakley F, Wilson L, Baker A, Russell OM, Johnson R, Richardson CA, Gupta B, McCallum I, McDonald SAC, Kelly S, Mathers JC, Heer R, Taylor RW, Perkins ND, Turnbull DM, Sansom OJ, Greaves LC. Age-associated mitochondrial DNA mutations cause metabolic remodeling that contributes to accelerated intestinal tumorigenesis. Nature Cancer 2020, 1, 976-989.
• Worrell J, Leslie J, Smith GR, Zaki M, Paish H, Knox A, James ML, Cartwright TN, OReily S, Kania G, Distler O, Distler J, Herrick A, Jeziorska M, Borthwick LA, Fisher AJ, Mann J, Mann DA, Oakley F. cRel expression regulates distinct transcriptional and functional profiles driving fibroblast matrix production in systemic sclerosis. Rheumatology 2020, 59(12), 3939-3951.
• Leslie J, Garcia Macia M, Luli S, Worrell JC, Reilly W, Paish HL, Knox A, Barksby BS, Gee LM, Zaki MYW, Collins A, Burgoyne RA, Cameron R, Bragg C, Xu X, Chung GW, Brown CDA, Blanchard AD, Nanthakumar CB, Karsdal M, Robinson SM, Manas DM, Sen G, French J, White SA, Murphy S, Trost M, Zakrzewski JL, Klein U, Schwabe RF, Mederacke I, Nixon C, Bird T, Teuwen LA, Schoonjans L, Carmeliet P, Mann J, Fisher AJ, Sheerin NS, Borthwick LA, Mann DA, Oakley F. c-Rel orchestrates energy-dependant epithelial and macrophage reprogramming in fibrosis. Nature Metabolism 2020, 2, 1350-1367.
• Leslie J, Millar BJM, del Carpio Pons A, Burgoyne RA, Frost JD, Barksby BS, Luli S, Scott J, Simpson JA, Gauldie J, Murray LA, Finch DK, Carruthers AM, Ferguson J, Sleeman MA, Rider D, Howarth R, Fox C, Oakley F, Fisher AJ, Mann DA, Borthwick LA. FPR-1 is an important regulator of neutrophil recruitment and a tissue-specific driver of pulmonary fibrosis. JCI Insight 2020, 5(4), e125937.
• Cairns JT, Habgood A, Edwards-Pritchard RC, Joseph C, John AE, Wilkinson C, Stewart ID, Leslie J, Blaxall BC, Susztak K, Alberti S, Nordheim A, Oakley F, Jenkins G, Tatler AL. Loss of ELK1 has differential effects on age-dependent organ fibrosis. The International Journal of Biochemistry & Cell Biology 2020, 120, 105668.
• Paish H, Reed L, Brown H, Bryan M, Govaere O, Leslie J, Barksby B, GarciaMacia M, Watson A, Xu X, Zaki M, Greaves L, Whitehall J, French J, White S, Manas D, Robinson S, Spoletini G, Griffiths C, Mann DA, Borthwick LA, Drinnan M, Mann J, Oakley F. A bioreactor technology for modelling fibrosis in human and rodent precision-cut liver slices. Hepatology 2019, 70(4), 1377-1391.
• De Chiara F, Thomsen KL, Habtesion A, Jones H, Davies N, Gracia-Sancho J, Manicardi N, Hall A, Andreola F, Paish HL, Reed LH, Watson AA, Leslie J, Oakley F, Rombouts K, Mookerjee RP, Mann J, Jalan R. Ammonia Scavenging Prevents Progression of Fibrosis in Experimental Nonalcoholic Fatty Liver Disease. Hepatology 2019, (ePub ahead of Print).
• Sirbu D, Luli S, Leslie J, Oakley F, Benniston AC. Enhanced in vivo Optical Imaging of the Inflammatory Response to Acute Liver Injury in C57BL/6 Mice using a Highly Bright Near-Infrared BODIPY Dye. ChemMedChem 2019, 14(10), 995-999.
• Malehmir M, Pfister D, Gallage S, Szydlowska M, Inverso D, Kotsiliti E, Leone V, Peiseler M, Surewaard BGJ, Rath D, Ali A, Wolf MJ, Drescher H, Healy ME, Dauch D, Kroy D, Krenkel O, Kohlhepp M, Engleitner T, Olkus A, Sijmonsma T, Volz J, Deppermann C, Stegner D, Helbling P, Nombela-Arrieta C, Rafiei A, Hinterleitner M, Rall M, Baku F, Borst O, Wilson CL, Leslie J, O'Connor T, Weston CJ, Adams DH, Sheriff L, Teijeiro A, Prinz M, Bogeska R, Anstee N, Bongers MN, Notohamiprodjo M, Geisler T, Withers DJ, Ware J, Mann DA, Augustin HG, Vegiopoulos A, Milsom MD, Rose AJ, Lalor PF, Llovet JM, Pinyol R, Tacke F, Rad R, Matter M, Djouder N, Kubes P, Knolle PA, Unger K, Zender L, Nieswandt B, Gawaz M, Weber A, Heikenwalder M. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nature Medicine 2019, 25(4), 641-655.
• Zeybel M, Luli S, Sabater L, Hardy T, Oakley F, Leslie J, Page A, Salvador EM, Sharkey V, Tsukamoto H, Chu DCK, Singh US, Ponzoni M, Perri P, Di Paolo D, Mendivil EJ, Mann J, Mann DA. A Proof-of-Concept for Epigenetic Therapy of Tissue Fibrosis: Inhibition of Liver Fibrosis Progression by 3-Deazaneplanocin A. Molecular Therapy 2017, 25(1), 218-231.
• Luli S, Di Paolo D, Perri P, Brignole C, Hill SJ, Brown H, Leslie J, Marshall HL, Wright MC, Mann DA, Ponzoni M, Oakley F. A new fluorescence-based optical imaging method to non-invasively monitor hepatic myofibroblasts in vivo. Journal of Hepatology 2016, 65(1), 75-83.
• Moles A, Butterworth JA, Sanchez A, Hunter JE, Leslie J, Sellier H, Tiniakos D, Cockell SJ, Mann DA, Oakley F, Perkins ND. A RelA(p65) Thr505 phospho-site mutation reveals an important mechanism regulating NF-kB dependent liver regeneration and cancer. Oncogene 2016, 35(35), 4623-4632.
• Hunter JE, Leslie J, Perkins ND. c-Rel and its many roles in cancer: an old story with new twists. British Journal of Cancer 2016, 114(1), 1-6.
• Fox C, Cocchiaro P, Oakley F, Howarth R, Callaghan K, Leslie J, Luli S, Wood KM, Genovese F, Sheerin NS, Moles A. Inhibition of lysosomal protease cathepsin D reduces renal fibrosis in murine chronic kidney disease. Scientific Reports 2016, 6, 20101.
• Wilson CL, Murphy LB, Leslie J, Kendrick S, French J, Fox CR, Sheerin NS, Fisher A, Robinson JH, Tiniakos DG, Gray DA, Oakley F, Mann DA. Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease. Journal of Hepatology 2015, 63(6), 1421-1428.