The main focus of our laboratory is to define how signal transduction by cytokines can modulate tissue homeostasis, and to understand how deregulation of these signalling pathways can promote numerous diseases, including cancer.
We use cell biology, molecular biology and structural biology techniques to understand how cytokines enable cancers to grow, metastasise and develop resistance to current treatments.
Our goal is to use the knowledge gained to facilitate the development of new therapeutic opportunities.
New Zealand, University of Canterbury, PhD
Canada, University of Toronto, BSc (Hons)
2020-2025 Silvia & Charles Viertel Charitable Foundation Senior Medical Research Fellow
2017 Australian Society for Medical Research, Peter Doherty Leading Light Award
2017-2020 Victorian Cancer Agency Fellow
2015-2019 Dyson Bequest Centenary Fellow
2022 CUREator, MRFF funding awarded through Brandon BioCatalyst (co-founder, Nelcanen Therapeutics)
2023-2026 Australian Research Council Discovery Project
2023-2025 Cancer Council Victoria Venture Grant
2011-2022 Multiple Project Grants, National Health and Medical Research Council
2020-2021 Accelerator Grant, Pankind
2018-2019 Accelerator Grant, Avner Foundation
2014-2017 Project Grant, Worldwide Cancer Research, United Kingdom
Current Member: Australian Living Organoid Alliance; Australian Gastrointestinal Trials Group; Australian Society for Medical Research; International Cytokine and Interferon Society
Formal mentor: Career Trackers Indigenous Women in STEM
Editorial board member: Cytokine, Frontiers Immunology
Chen YH, Zastrow DB, Metcalfe RD, Gartner L, Krause F, Morton CJ, Marwaha S, Fresard L, Huang Y, Zhao C, McCormack C, Bick D, Worthey EA, Eng CM, Gold J, Undiagnosed Diseases Network, Montgomery SB, Fisher PG, Ashley EA, Wheeler MT, Parker MW, Shanmugasundaram V, Putoczki TL, Schmidt-Arras D, Laurence A, Bernstein JA, Griffin MDW, Uhlig HH. Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome. J Allergy Clin Immunol. 2021 Aug;148(2):585-598. doi: 10.1016/j.jaci.2021.02.044. Epub 2021 Mar 23. PMID: 33771552
Low JT, Christie M, Ernst M, Dumoutier L, Preaudet A, Ni Y, Griffin MDW, Mielke LA, Strasser A, Putoczki TL#, O’Reilly LA# Loss of NFKB1 Results in Expression of Tumor Necrosis Factor and Activation of Signal Transducer and Activator of Transcription 1 to Promote Gastric Tumorigenesis in Mice. Gastroenterology. 2020 Jun 20:S0016-5085(20)34840-X. doi: 10.1053/j.gastro.2020.06.039. PMID: 32569771
Metcalfe RD, Aizel K, Zlatic CO, Nguyen PM, Morton CJ, Lio DS, Cheng HC, Dobson RCJ, Parker MW, Gooley PR, Putoczki TL#, Griffin MDW# The structure of the extracellular domains of human interleukin 11α receptor reveals mechanisms of cytokine engagement. J Biol Chem. 2020 Jun 12;295(24):8285-8301. doi: 10.1074/jbc.RA119.012351. Epub 2020 Apr 24. PMID: 32332100
Ziegler PK, Bollrath J, Pallangyo CK, Matsutani T, Canli Ö, De Oliveira T, Diamanti MA, Müller N, Gamrekelashvili J, Putoczki T, Horst D, Mankan AK, Öner MG, Müller S, Müller-Höcker J, Kirchner T, Slotta-Huspenina J, Taketo MM, Reinheckel T, Dröse S, Larner AC, Wels WS, Ernst M, Greten TF, Arkan MC, Korn T, Wirth D, Greten FR. Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis. Cell. 2018 Jun 28;174(1):88-101.e16. doi: 10.1016/j.cell.2018.05.028. PMID: 29909986
O’Reilly LA, Putoczki TL*, Mielke LA, Low JT, Lin A, Preaudet A, Herold MJ, Yaprianto K, Tai L, Kueh A, Pacini G, Ferrero RL, Gugasyan R, Hu Y, Christie M, Wilcox S, Grumont R, Griffin MDW, O’Connor L, Smyth GK, Ernst M, Waring P, Gerondakis S, Strasser A. Loss of NF-κB1 Causes Gastric Cancer with Aberrant Inflammation and Expression of Immune Checkpoint Regulators in a STAT-1-Dependent Manner. Immunity. 2018 Mar 20;48(3):570-583.e8. doi: 10.1016/j.immuni.2018.03.003. PMID: 29562203 *Joint first author
Poh AR, Love CG, Masson F, Preaudet A, Tsui C, Whitehead L, Monard S, Khakham Y, Burstroem L, Lessene G, Sieber O, Lowell C, Putoczki TL*, O’Donoghue RJJ, Ernst M. Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression. Cancer Cell. 2017 Apr 10;31(4):563-575.e5. doi: 10.1016/j.ccell.2017.03.006. PMID: 28399411 *Joint senior author
Schafer S, Viswanathan S, Widjaja AA, Lim WW, Moreno-Moral A, DeLaughter DM, Ng B, Patone G, Chow K, Khin E, Tan J, Chothani SP, Ye L, Rackham OJL, Ko NSJ, Sahib NE, Pua CJ, Zhen NTG, Xie C, Wang M, Maatz H, Lim S, Saar K, Blachut S, Petretto E, Schmidt S, Putoczki T, Guimarães-Camboa N, Wakimoto H, van Heesch S, Sigmundsson K, Lim SL, Soon JL, Chao VTT, Chua YL, Tan TE, Evans SM, Loh YJ, Jamal MH, Ong KK, Chua KC, Ong BH, Chakaramakkil MJ, Seidman JG, Seidman CE, Hubner N, Sin KYK, Cook SA. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature. 2017 Dec 7;552(7683):110-115. doi: 10.1038/nature24676 PMID: 29160304
Putoczki TL, Dobson RC, Griffin MD. The structure of human interleukin-11 reveals receptor-binding site features and structural differences from interleukin-6. Acta Crystallogr D Biol Crystallogr. 2014 Sep;70(Pt 9):2277-85. doi: 10.1107/S1399004714012267. PMID: 25195742
Putoczki TL, Thiem S, Loving A, Busuttil RA, Wilson NJ, Ziegler PK, Nguyen PM, Preaudet A, Farid R, Edwards KM, Boglev Y, Luwor RB, Jarnicki A, Horst D, Boussioutas A, Heath JK, Sieber OM, Pleines I, Kile BT, Nash A, Greten FR, McKenzie BS, Ernst M. Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer cell. 2013 Aug 12;24(2):257-71. PMID: 23948300
We have specific expertise in Interleukin (IL)-11, a member of the IL-6 family of pleiotropic cytokines. IL-11 signalling is initiated following binding to its membrane bound, cell-type specific receptor, IL-11R. This binary complex engages a transmembrane receptor called GP130, inducing dimerisation and activation of numerous transcription factors, including STAT3. STAT3 has been implicated in the maintenance of a tumour-promoting microenvironment, and persistent STAT3 activation is a feature of many human cancers of both haematopoietic and epithelial origin.
We are part of a multi-institutional collaborative project that was the first to solve the structure of the human IL-11 ligand, receptor and the authentic signalling complex. We build on this knowledge to understand the evolution of cytokine signalling, relationships to disease, and to enable therapeutic development.
A common feature of all tumours is the bi-directional interactions between tumour cells and the stroma, whereby tumour cells can stimulate the inflamed stroma, which in turn can enhance the malignant traits of tumour cells. This self-amplifying feedback loop is fuelled by cytokines. For this reason, the concept of combating tumour progression, through inhibition of growth promoting cytokines present in the tumour microenvironment is becoming of great therapeutic interest.
We are combining laboratory models and patient clinical data to understand the role of cytokines in multiple cancers including the brain, colon, lung and pancreatic cancer and how they promote resistance to standard-of-care therapies, targeted therapies and immunotherapies.
Inflammatory bowel disease patients have an increased risk of colorectal cancer (CRC). CRC is the forth most common cause of malignancy worldwide. Alarmingly, the highest incidence rates occur in Australia, where CRC is the second most common cause of cancer-related deaths.
We are establishing new laboratory models to characterise novel proteins that are associated with human inflammatory bowel disease and the development of CRC. Our focus is on drug development and stratification of patients for treatment.
Together with a team of clinical and scientific collaborators, we have built a personalised treatment platform for pancreatic cancer, consisting of a tissue biobank and an extensive collection of patient-derived organoids (PDOs) and patient-derived xenografts (PDXs). PDOs are small 3-D cell clusters that are generated from biopsies or from surgically resected pancreatic cancers. Our collection covers the full disease spectrum – from early-stage lesions through to metastatic disease. The advantage of PDOs is that they mirror tumour architecture and can be used to test the efficacy of multiple new drugs in parallel. We were the first to generate a pancreatic cancer PDO biobank in Australia (a collaboration between WEHI and the University of Melbourne). We have validated that PDOs are an excellent patient tumour replica, as their response to chemotherapy matches that of the patient from which they were derived.
Over the last 40+ years very few new drugs have been approved, yielding little improvement in pancreatic patient outcomes. Our goal is to continue to develop new model systems to empower personalised medicine, enabling screening for new drugs, combinations treatments, and identification of the patients most likely to respond.