Super Content: 
Developing intestinal buds, colours highlight the proteins involved in growth

Dr Tracy Putoczki presents her research findings into targeting cytokines in inflammatory diseases with a focus on Interkeukin-11.

Defining the mechanism of signalling by cytokines

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.

Examining how cytokines promote tumour growth, invasion and metastasis

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 current standard-of-care therapies.

Developing new modalities for pre-clinical imaging of inflammatory bowel disease and cancer

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 imaging technologies and laboratory models to characterise novel proteins that are associated with human inflammatory bowel disease and the development of CRC.

Developing truly personalised pre-clinical models for drug development

Together with a team of clinical and scientific collaborators, we have built a personalised treatment platform for pancreatic, consisting of a tissue biobank and an extensive collection of patient-derived organoids (PDOs). 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 (funded by the AVNER Foundation, 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.