How does necrotic cell death contribute to colorecal cancer

Lead researcher

Dr James Murphy, Dr Silvia Alvarez-Diaz, A/Prof Matthias Ernst

Dr James Murphy, Dr Silvia Alvarez-Diaz, A/Prof Matthias Ernst

Institution
The Walter and Eliza Hall Institute of Medical Research

Tumour type:
Bowel

Years funded
2015-2017

Project description

Inflammation is widely recognised as an essential component of tumour development, and the link between inflammation and initiation, progression and metastasis of bowel cancer is now well established.

Necroptosis has emerged as a novel process of programmed cell death with the ability to modulate inflammatory responses. We have recently shown a key role for the protein MLKL in the necroptosis pathway; however, the contribution of necrosptosis to bowel cancer remains unknown.

Based on our preliminary results we hypothesise that activation of the necroptosis pathway favours a pro-inflammatory environment that promotes tumour initiation and fuels tumour growth. To test this we are using complementary pre-clinical models of intestinal inflammation to genetically manipulate MLKL expression and stufy its role. 

What is the need? 

Bowel cancer is the second most common type of newly diagnosed cancer in Australia. Unfortunately, a small number of bowel cancers are detected in early stages, and once it's spread to other parts of the body, current therapies are ineffective.

Our functional assessment of the contribution of necroptosis/ MLKL in a comprehensive collection of clinically highly relevant models will provide strong evidence on which we can translate our findings into the clinic to improve outcomes for patients. 

What impact will this research have?

The insight from our proposed research will have an immediate translational impact by providing strong proof-of-principle evidence for the role of necroptosis in the development of bowel cancer.

We need to know how we can fight against cancer more efficiently. Personalised, target and combinatorial therapies are the future and our research will bring better understanding of how we can use different strategies to fight against cancer. 

 

Project timeline

20152016 
2017 

   We studied the role of necroptosis in models of bowel cancer and found that our protein of interest, MLKL, has a protective role against bowel cancer induced by the carcinogen AOM.   

 
We established pre-clinical models and expanded our knowledge of the effect of MLKL. Complete our studies and compile information to send for publication.

 

"Personalised, targeted and combinatorial therapies are the future and our research will bring better understanding of how we can use different strategies to fight against cancer."