Researchers in the Tiganis lab investigate the mechanisms by which obesity and metabolism influence the development of cancer.

Excess body weight is a major and leading factor in overall disease burden. In 2010 overweight and obesity were estimated to cause some 3.4 million deaths worldwide. Obesity is a key contributor to a myriad of human diseases, including cancer.

In developed countries it is estimated that approximately 20% of cancer deaths in women and 14% of cancer deaths in men are linked to obesity. Overall cancer burden is expected to double over the next 10-20 years as a direct consequence of the obesity epidemic.

Obesity increases the risk for varied human malignancies, including endometrial cancer, esophageal cancer, pancreatic cancer, post-menopausal breast cancer, colorectal cancer and liver cancer.

For example the relative risk for endometrial cancer in women with a Body Mass Index (BMI) > 40 kg/m2 is increased by greater than 6 fold. Obesity has been estimated to account for up to 40-60% of endometrial cancer incidence in developed countries.

For men the greatest risk is hepatocellular carcinoma (HCC), where risk of mortality in men with BMIs of 35-40 40 kg/m2 is increased by 4.5-fold times.

The Tiganis laboratory has had a long-standing interest in delineating the CNS and peripheral mechanisms that contribute to the development of obesity and its associated complications.

A key focus of our recently established laboratory at the Peter MacCallum Cancer Centre is to understand how obesity drives the development of cancer, including HCC, endometrial cancer and breast cancer.

More specifically, the Tiganis laboratory in interested in understanding the influence on redox balance and tumour metabolism and how obesity affects tumour immunology and immunotherapy.

Research projects

Targeting immune checkpoints in obesity-driven HCC

Supervisors: Prof. Tony Tiganis and Dr Florian Wiede

Hepatocellular carcinoma (HCC) is the most rapidly rising cause of cancer death in Australia. The obesity epidemic and the accompanying development of non-alcoholic fatty liver disease (NALFD) have become major drivers of HCC in the developed world. It is estimated that >85% of overweight individuals and 25.2% of the general population have NAFLD. If left unresolved, NAFLD can progress and result in severe fibrosis or cirrhosis and HCC. At present there are no effective therapies for advanced NAFLD with severe fibrosis/cirrhosis. Moreover, although surgical resection and liver transplantation are effective for early stage HCC, the majority of patients present with advanced disease, when neither surgery, chemotherapy, ionizing radiation or targeted therapies (Sorafenib) are effective. Thus, there is an urgent need for the development of effective therapeutics. Pre-clinical studies point towards the suppression of the immune system being fundamental for HCC development in obesity/NAFLD. However, recent phase III trials for HCC have been disappointing, with the Merck’s PD-1 blocking antibody Keytruda (pembrolizumab) failing to achieve any significant improvements in survival.

Our pilot studies suggest that the lack of efficacy of anti-PD-1 monotherapy in HCC might be due to HCC engaging multiple redundant immune checkpoints and posit that the combinatorial targeting of several immune checkpoints will be necessary to combat HCC in obesity. Projects are available to assess the therapeutic potential of targeting multiple immune checkpoints in the context of NAFLD driven HCC.

Using T cells to eradicate cancer

Supervisors: Prof. Tony Tiganis and Dr Florian Wiede

The inability of the adaptive immune system to initiate a robust anti-tumour response is often linked to the poor prognosis of patients. Immunotherapy is poised to play a central role in the treatment of varied human cancers. The project will take advantage of multidisciplinary techniques and utilise both cell-based and animal models to develop novel approaches for enhancing cytotoxic T cell responses in the context of T cell adoptive immunotherapy.

Understanding how obesity drives the development of liver cancer

Supervisors: Prof. Tony Tiganis and Dr Florian Wiede

Obesity is a leading factor in the development of liver disease, with >85% of overweight individuals developing non-alcoholic fatty liver disease (NAFLD). NAFLD encompasses a broad spectrum of liver conditions ranging from simple steatosis, to the more severe and progressive non-alcoholic steatohepatitis (NASH), a condition that results in fibrosis and if left unresolved, cirrhosis (late stage liver disease) and/or liver cancer. Obesity-associated NASH is currently the third leading cause for liver transplantation and is expected to soon surpass hepatitis C as the principal cause for liver transplantation and hepatocellular carcinoma (HCC) in the developed world. Projects are available to determine the mechanisms by which obesity drives the development of NASH, fibrosis and HCC.

People

Dr Florian Wiede, Senior Research Officer; Theme Leader
Mara Zeissig , Post Doc
Xin Du, PhD Student
Pei Kee Goh , Post Doc
Rachel Xu, Research Assistant
Shuwei Liang, PhD Student
Nan Hu, PhD Student
Teresa Tiganis, Visiting Scientist

Key publications

Metabolism

Loh K, Deng H, Fukushima A, Cai X, Boivin B, Galic S, Bruce C, Shields BJ, Skiba B, Ooms L, Stepto N, Wu B, Mitchell CA, Tonks NK., Watt MJ, Febbraio MA, Crack PJ, Andrikopoulos S, and Tiganis T (2009). Reactive oxygen species enhance insulin sensitivity. Cell Metabolism.10 (4): 260-272.

Gurzov EN, Tran M, Fernandez-Rojo MA, Merry TL, Zhang X, Yu Y, Fukushima A, Waters MJ, Watt MJ, Andrikopoulos S, Neel BG, Tiganis T (2014) Hepatic Oxidative Stress Promotes insulin-STAT-5 Signaling and Obesity by Inactivating Protein Tyrosine Phosphatase N2Cell Metabolism. 20(1), 85-102.

Dodd GT, Decherf S, Loh K, Simonds SE, Wiede F, Balland E, Merry TL, Münzberg H, Zhang ZY, Kahn BB, Neel BG, Bence KK, Andrews ZB, Cowley MA, Tiganis T (2015). Leptin and Insulin Act on POMC Neurons to Promote the Browning of White Fat. Cell. 160(1-2):88-104.

Dodd GT Andrews ZB, Simonds S, Michael NJ, DeVeer M, Brüning JC, Spanswick D, Cowley MA, and Tiganis T (2017). A hypothalamic phosphatase switch coordinates energy expenditure with feeding. Cell Metabolism. 26(2): 375-393.

Quinn KM, Fox A, Harland KL, Russ BE, Li J, Nguyen THO, Loh L, Olshanky M, Naeem H, Tsyganov K, Wiede F, Webster R, Blyth C, Sng XYX, Tiganis T, Powell D, Doherty PC, Turner SJ, Kedzierska K, Gruta NLL. (2018) Age-Related Decline in Primary CD8 + T Cell Responses Is Associated With the Development of Senescence in Virtual Memory CD8 + T CellsCell Reports. 23(12), 3512-3524. 

Cancer

Shields B, Hauser C, Bukczynska PE, Court NW, and Tiganis T (2008). DNA replication stalling attenuates tyrosine kinase signalling to suppress S-phase progression. Cancer Cell.14(2):166–179.

Shields BJ, Wiede F, Gurzov EN, Wee K, Hauser C, Zhu HJ, Molloy TJ, O’Toole SA, Daly RJ, Sutherland RL, Mitchell CA, McLean CA, and T. Tiganis (2013). TCPTP regulates SFK and STAT3 signalling and is lost in triple negative breast cancers. Molecular Cell Biology. 33, 557-570

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 (2018). Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. Cell. 175(5), 1289-1306.

Wiede F, Lu KH, Du X, Liang S, Hochheiser K, Dodd GT, Goh PK, Kearney C, Meyran D, Beavis PA, Henderson MA, Park SL, Waithman J, Zhang S, Zhang ZY, Oliaro J, Gebhardt T, Darcy PK, Tiganis T. (2020) PTPN2 Phosphatase Deletion in T Cells Promotes Anti-Tumour Immunity and CAR T-cell Efficacy in Solid Tumours. The EMBO Journal. 39(2). 

Immunity

Wiede F, Shields BJ, Chew SH, Kyparissoudis K, van Vliet C, Galic S, Tremblay ML, Russell SM, Godfrey DI, and T Tiganis. (2011). T cell protein tyrosine phosphatase attenuates T cell signaling for the maintenance of tolerance in mice. The Journal of Clinical Investigations. 121(12):4758-74.

Wiede F, Gruta NLL, Tiganis T (2014) PTPN2 Attenuates T-cell Lymphopenia-Induced ProliferationNature Communication. 

Wiede F, Dudakov JA, Lu KH, Dodd GT, Butt T, Godfrey DI, Strasser A, Boyd RL, Tiganis T (2017). PTPN2 regulates T cell lineage commitment and ab versus gd specification. Journal of Experimental Medicine. 214(9):2733-2758.

Twohig JP, Figueras AC, Andrews R, Wiede F, Cossins BC, Soria AD, Lewis MJ, Townsend MJ, Millrine D, Li J, Hill DG, Fernandez JU, Liu X, Szomolay B, Pepper CJ, Taylor PR, Pitzalis C, Tiganis T, Williams NM, Jones GW, Jones SA (2019) Activation of naïve CD4 + T Cells Re-Tunes STAT1 Signaling to Deliver Unique Cytokine Responses in Memory CD4 + T CellsNature Immunology. 20(4), 458-470. 

Wiede F, Brodnicki TC, Goh PK, Leong YA, Jones GW, Yu D, Baxter AG, Jones SA, Kay TWH, Tiganis T (2019) T-Cell-Specific PTPN2 Deficiency in NOD Mice Accelerates the Development of Type 1 Diabetes and Autoimmune ComorbiditiesDiabetes. 68(6), 1251-1266. 

Svensson MNd, Doody KM, Schmiedel BJ, Bhattacharyya S, Panwar B, Wiede F, Yang S, Santelli E, Wu DJ, Sacchetti C, Gujar R, Seumois G, Kiosses WB, Aubry I, Kim G, Mydel P, Sakaguchi S, Kronenberg M, Tiganis T, Tremblay ML, Ay F, Vijayanand P, Botti N. (2019) Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity. The Journal of Clinical Investigations. 129(3), 1193-1210.

Research programs