Liver Dysfunction and Cancer Development

Liver cancer is the fourth leading cause of cancer-related mortality worldwide. Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, accounts for approximately 90% of all cases and is associated with a five-year survival rate of only around 15%.

Obesity is characterized by profound metabolic dysregulation and chronic low-grade inflammation, both of which contribute to liver disease progression. The transition from Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) to Metabolic dysfunction-associated steatohepatitis (MASH) and ultimately HCC is driven by a complex interplay of metabolic stress, genetic susceptibility, and environmental influences. However, the molecular mechanisms that determine why only a subset of individuals with obesity develop HCC remain poorly understood.

HCC remains highly resistant to most currently available anticancer therapies, underscoring the urgent need for improved prevention and treatment strategies. In addition, there are currently no reliable approaches to identify individuals with obesity who are at high risk of developing HCC.

Group Leader, Esteban Gurzov, Ph.D.

Research Interests

Deciphering metabolic drivers of obesity-associated liver cancer

Our research aims to understand why only a subset of individuals with obesity develop HCC, despite the widespread occurrence of metabolic liver disease. We investigate how obesity-induced metabolic dysfunction reprograms liver cells during the progression from MASLD to MASH and ultimately liver cancer. By integrating analyses of human liver biopsies, advanced omics technologies, and experimental disease models, we identify the molecular pathways that drive malignant transformation and reveal biomarkers associated with disease progression.

A major focus of our laboratory is the role of protein tyrosine phosphatases (PTPs), a family of signalling enzymes that regulate cellular metabolism and inflammatory responses. Our work has demonstrated that altered activity of specific PTPs, including PTPRK and PTPRF, promotes metabolic reprogramming in hepatocytes by enhancing glycolysis, lipogenesis, and other pathways that fuel tumour growth. Using genetically engineered mouse models, human stem cell-derived hepatocytes, liver organoids, and patient samples, we investigate how these enzymes control liver metabolism and contribute to obesity-associated HCC.

Beyond understanding disease mechanisms, we are developing innovative therapeutic strategies targeting these newly identified metabolic regulators. Our laboratory combines computational drug discovery, medicinal chemistry, and functional validation to develop selective inhibitors against disease-promoting phosphatases. By targeting the molecular pathways that initiate metabolic dysfunction and tumour development, we aim to establish new approaches for the prevention, early detection, and treatment of obesity-associated liver cancer, ultimately improving outcomes for patients with this devastating disease. (Figure adapted from Gilglioni EH, et al. Nature Communications 2024)

Diagram illustrating the process of fatty acid synthesis, showing stages such as Obesity, Lipogenesis, Glycolysis, PPAR, FBP1, and HCC, represented by interconnected gears and a pointing hand.

Selected Publications

  1. Gilglioni EH, Li A, St-Pierre-Wijckmans W, Shen TK, Pérez-Chávez I, Hovhannisyan G, Lisjak M, Negueruela J, Vandenbempt V, Bauzá-Martinez J, Herranz JM, Ezerina E, Demine S, Feng Z, Vignane T, Otero-Sánchez L, Lambertucci F, Prašnická A, Devière J, Hay DC, Encinar JA, Singh SP, Messens J, Filipovic MR, Sharpe HJ, Trépo E, Wu W, Gurzov EN. Protein tyrosine phosphatase receptor kappa regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity. Nature Communications, 15(01):9522, 2024

  2. Pérez-Chávez I, Koberstein JN, Pueyo JM, Gilglioni EH, Vertommen D, Baeyens N, Ezeriņa D, Gurzov EN, Messens J. Tracking fructose 1,6-bisphosphate dynamics in liver cancer cells using a fluorescent biosensor. iScience 27(12):111336, 2024

  3. Talamantes S, Lisjak M, Gilglioni EH, Llamoza-Torres CJ, Ramos-Molina B, Gurzov EN. Non-alcoholic fatty liver disease and diabetes mellitus as growing aetiologies of hepatocellular carcinoma. JHEP Rep 5(9):100811, 2023

  4. Brahma MK, Gilglioni EH, Zhou L, Trepo E, Chen P, Gurzov EN. Oxidative Stress in Obesity-Associated Hepatocellular Carcinoma : Sources, Signaling and Therapeutic Challenges. Oncogene 40(33):5155-5167, 2021

  5. Grohmann M, Wiede F, Dodd GT, Gurzov EN, Ooi GJ, Butt T, Rasmiena AA, Kaur S, Gulati T, Goh PK, Treloar AE, Archer S, Brown WA, Muller M, Watt MJ, Ohara O, McLean CA, Tiganis T. Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. Cell 175(5):1289-1306, 2018

  6. Litwak SA, Pang L, Galic S, Igoillo-Esteve M, Stanley WJ, Turatsinze JV, Loh K, Thomas HE, Sharma A, Trepo E, Moreno C, Gough DJ, Eizirik DL, de Haan JB, Gurzov EN. JNK Activation of BIM Promotes Hepatic Oxidative Stress, Steatosis and Insulin Resistance in Obesity. Diabetes 66:2973-2986, 2017

  7. Gurzov EN, Stanley WJ, Brodnicki TC, Thomas HE. Protein tyrosine phosphatases: molecular switches in metabolism and diabetes. Trends Endocrinol Metab 26(1):30-39, 2015

  8. Gurzov EN, Tran M, Fernandez-Rojo M, Merry T, Zhang X, Xu Y, Fukushima A, Waters MJ, Watt M, Andrikopoulos S, Neel BG, Tiganis T. Hepatic oxidative stress promotes insulin-STAT5 signaling and obesity by inactivating PTPN2. Cell Metabolism 20(1):85-102, 2014

 

Support our research

You have the opportunity to become a supporter of the work being undertaken at the Signal Transduction & Metabolism Laboratory - your support will help the new generation of junior researchers become experienced scientists and may make a difference in the search of better treatments for diabetes and liver cancer.

Please Donate
Signal Transduction and Metabolism Laboratory