Prof Tom Bird - Liver Cancer, Disease and Regeneration

Introduction

Liver cancer is the third most common cause of cancer-related death worldwide. It is becoming an increasing problem, particularly in the Western world, and its rates have trebled in Scotland in the last 20 years. Despite some improvements in outcomes for those patients in whom the disease is detected early, there remains a limited range of only minimally effective treatment options for the overwhelming majority of patients who have their disease detected at a later stage. Precision medicine offers the potential to target more effective therapies to individuals with different forms of this disease, across this highly heterogeneous cancer.

My group has been interested in studying the regenerative responses to injury and aberrant proliferative responses in cancer of hepatocytes, the principle functional cell of the liver. These cells show immense regenerative capacity but are also the source of the most common primary liver cancer, hepatocellular carcinoma (HCC).

We have described how these cells enter a state of shock, named senescence, in response to injury, and how preventing them from doing so can promote liver regeneration. We are also investigating how this same senescent state occurs during early cancer formation as an anti- cancer therapeutic target.

To further understand these processes, we have developed a state-of-the-art suite of genetically engineered models of HCC, which mimics key features of the human condition. This suite is based upon the range of genetic mutations which drive HCC across the spectrum of human disease. Cross comparing between the models and patients we are able to identify novel pathways for therapy and some drug combinations which are highly effective in our cancer models. Working with academic and industrial collaborators, we are using these avatar-like models to uncover and test novel therapies, which could be used to target precision medicine dependent on the underlying characteristics of tumours in different patients.

Exposing liver cancer

Read about Tom's collaboration with the University of Edinburgh's Centre for Statistics to improve early detection of liver cancer here.

Other funding:

Lab Report

pdf Bird Lab Report (162 KB)

Key Publications

Nehme J, Borghesan M, Mackedenski S, Bird TG, Demaria M. Cellular senescence as a potential mediator of COVID-19 severity in the elderly. Aging Cell. 2020:e13237.

Müller M, Bird TG, Nault J-C. The landscape of gene mutations in cirrhosis and hepatocellular carcinoma. J Hepatol. 2020; 72: 990-1002

Hughes DM, Berhane S, Degroot ECA, Toyoda H, Tada T, Kumada T, Satomura S, Nishida N, Kudo M, Kimura T, Osaki Y, Kolamunage-Dona R, Salvador RA, Bird TG, Fiñana MG, Johnson P. Serum Levels of Alpha Fetoprotein Increased More Than 10 Years Before Detection of Hepatocellular Carcinoma. Clin Gastroenterol Hepatol. 2020;19:162-170

Vizioli MG, Liu T, Miller KN, Robertson NA, Gilroy K, Lagnado AB, Perez-Garcia A, Kiourtis C, Dasgupta N, Lei X, Kruger PJ, Nixon C, Clark W, Jurk D, Bird TG, Passos JF, Berger SL, Dou Z, Adams PD. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes & development. 2020; 34: 428-445

Amoros R, King R, Toyoda H, Kumada T, Johnson PJ, Bird TG. A continuous-time hidden Markov model for cancer surveillance using serum biomarkers with application to hepatocellular carcinoma. Metron. 2019;77:67-86.

Teo YV, Rattanavirotkul N, Olova N, Salzano A, Quintanilla A, Tarrats N, Kiourtis C, Muller M, Green AR, Adams PD, Acosta JC, Bird TG, Kirschner K, Neretti N, Chandra T. Notch Signaling Mediates Secondary Senescence. Cell Rep 2019; 27: 997-1007

Gay DM, Ridgway RA, Mueller M, Hodder MC, Hedley A, Clark W, Leach JD, Jackstadt R, Nixon C, Huels DJ, Campbell AD, Bird TG, Sansom OJ. Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer. Nature communications 2019; 10: 723.

Bird TG, Muller M, Boulter L, Vincent DF, Ridgway RA, Lopez-Guadamillas E, Lu WY, Jamieson T, Govaere O, Campbell AD, Ferreira-Gonzalez S, Cole AM, Hay T, Simpson KJ, Clark W, et al. TGFbeta inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci Transl Med 2018; 10: eaan1230

Bird TG, Dimitropoulou P, Turner RM, Jenks SJ, Cusack P, Hey S, Blunsum A, Kelly S, Sturgeon C, Hayes PC, Bird SM. Alpha-Fetoprotein Detection of Hepatocellular Carcinoma Leads to a Standardized Analysis of Dynamic AFP to Improve Screening Based Detection. PLoS One 2016; 11: e0156801.

Lu WY, Bird TG, Boulter L, Tsuchiya A, Cole AM, Hay T, Guest RV, Wojtacha D, Man TY, Mackinnon A, Ridgway RA, Kendall T, Williams MJ, Jamieson T, Raven A, Hay DC, Iredale JP, Clarke AR, Sansom OJ, Forbes SJ. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol 2015; 17: 971-83.

Bird TG, Lu WY, Boulter L, Gordon-Keylock S, Ridgway RA, Williams MJ, Taube J, Thomas JA, Wojtacha D, Gambardella A, Sansom OJ, Iredale JP, Forbes SJ. Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling. PNAS 2013; 110: 6542-7.

Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N, Sansom OJ, Iredale JP, Lowell S, Roskams T, Forbes SJ. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nature Medicine 2012; 18: 572-9.

Hsieh WC, Mackinnon AC, Lu WY, Jung J, Boulter L, Henderson NC, Simpson KJ, Schotanus B, Wojtacha D, Bird TG, Hay D, Medine C, Sethi T, Iredale JP, Forbes SJ. Galectin-3 regulates hepatic progenitor cell expansion during liver injury. Gut 2015; 64: 312-21.

Lorenzini S*, Bird TG*, Boulter L, Bellamy C, Samuel K, Aucott R, Clayton E, Andreone P, Bernardi M, Golding M, Alison MR, Iredale JP, Forbes SJ. Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver. Gut 2010; 59: 645-54. *Joint first authorship