Complement Membrane Attack and Tumorigenesis

Immuno-oncology is a hot topic right now. Everyone is talking about it and money is pouring in to take advantage of this fantastic new approach. It is exciting to me because I have spent years working on understanding the role that inflammation plays in tumour development – you may have heard it referred to as a secondary hallmark of cancer. By understanding this biology, the hope is that we can get a grasp on the complex interplay between the immune system and developing tumours, a very important influencer on the effectiveness of immuno-oncology therapies.

My research focuses on how tumour cells respond to inflammatory signals and how that might influence tumour growth. I am particularly interested in an inflammatory system called complement, a system of proteins that act as an early warning  signal to alert the body when a foreign object is present. That includes pathogens, but can also include host cells that don’t appear to be normal. I want to understand if this system is capable of encouraging tumour growth and if so how does it do this.

Think of the signal arising from complement activation as a big stick prodding into the cells of a tumour. For decades there have been studies around the simple mechanisms of how a cell responds to such and we know more than ever. However, the complex way that cells behave when confronted with a multitude of signals is not a simple question. When complement activates and ‘prods’ the cell there is more than one thing happening. To answer the question of how the cell responds, one needs to account for all of these simple mechanisms together - to get to more than the sum of the parts. This is only achievable by measuring all the resulting changes and comparing them to existing knowledge in order to take a holistic view. This is what systems biology is all about.

In my research, I used a systems biology approach to look at all the changes to the cell to find the pattern that complement triggered and try to comprehend the influence this might have on tumour development. The resulting research paper outlines how you can analyze transcript level (RNA) data to understand the cellular response to complement. Importantly, the analysis focuses on using network analysis on the MetaCore platform to take existing knowledge of biological interactions and use them to get a global picture of the responses.

The paper resulted in a set of co-regulated networks that define the broader consequence of complement activation on tumours, bringing us closer to understanding the broader mechanism. It also provides a gene signature that may represent  a marker for complement activation on host cells, made up of genes which are likely to be involved in cell behaviours that can be considered cancer driving. This is yet more evidence of the importance of inflammation in tumour development, something that will be more and more important as we work towards developing immune-oncology therapies.

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