Professor Steven Pollard is a Senior Cancer Research Fellow at the CRUK Edinburgh Centre. His team is using innovative cell culture models to advance our understanding of brain stem cells and their potential role in glioblastoma.
Here Steve tells us how his interest in stem cells led him into cancer research and how he believes this angle of brain tumour research has unique potential for tackling cancers which are currently difficult to treat.
“I originally trained as a developmental biologist, then, during my postdoc in stem cell biology, I became interested in research showing that the growth of brain tumours might be driven by cells similar to neural stem cells. Neural stem cells have this remarkable ability to continuously self-renew and it seems brain tumour stem cells are exploiting some of the same molecular programs when they multiply, though in a very corrupted way.
As we’d been working hard optimising conditions to grow normal neural stem cells in the lab, the immediate question for me was could we grow brain cancer cells in the same way. Could we capture the patient’s disease in a dish? In 2004 I made the first attempts to grow cultures from primary human tumours. This worked much more easily than we expected. You could get cells directly from a patient’s tumour and the next day they would be growing nicely in the lab.
Disease in a dish
This was a real turning point in my career. The potential for this to be useful was obvious – both in understanding the molecular and cellular biology of the disease, but also for drug discovery and screening. To be able to grow a patient’s cancer and compare it with genetically normal neural stem cells is a really special tool. What had initially been a side project for me became the main focus of my research.
I was fortunate enough to secure a CRUK project grant – my first independent grant – which gave me the resources to take this project forward. I was also fortunate that my postdoctoral supervisor at that time was generous in letting me pursue something outside of the core interests of his lab. Then in early 2010 I set up my first independent lab at UCL, to build a bigger team within the Samantha Dickson Brain Cancer Unit at the UCL Cancer Institute.
We initially focused on drilling down into the genetic differences between glioblastoma tumour stem cells and normal neural stem cells. We looked at the different molecular and cell properties they had, how different drugs affected each – essentially comparing and contrasting the two cell types. We wanted to identify any differences that could be the key to fueling the relentless growth of the tumour.
In 2014 I relocated to Edinburgh and secured a CRUK Senior Cancer Research Fellowship, which has given me the freedom to explore some ambitious ideas, and enabled me to grow my research group with the security of six year funding.
The comparisons with normal neural stem cells we’d done proved really valuable. It became clear that certain neurodevelopmental transcription factors – the factors that tell a cell ‘you are a neural stem cell’ – are highly expressed in glioblastoma. These master regulators of cell identity include important developmental proteins, such as FOX and SOX families. It seems in cancer stem cells these genes become up regulated, producing excessive amounts of these transcription factors. This results in cells getting stuck in a perpetual state of renewal.
To differentiate or die
If brain tumours are driven by neural stem cells with faulty developmental pathways, these transcription factors could potentially be good drug targets. So one of the major questions we’re exploring is whether we can find proteins that can target the transcription factors and block this excessive production. If we destroy their activity will the tumour cells die or stop growing? However, it’s not easy to design small molecules against transcription factors – by their nature they don’t have a molecular structure we can easily design blocking chemicals against. Instead we are searching for key partners. Do they rely on any co-factors that are ‘druggable’? If we can crack this, we could stop stem cells being stuck in this perpetual renewing cycle. To get them instead to differentiate or die.
A big technical advance that’s made this goal feel more achievable is the development of CRISPR. It’s a real milestone – the sort of leap forward in technology you get only every 10 or 20 years.
CRISPR helps us to edit genes with unprecedented precision. It now means we are able to easily engineer molecular tags, or fluorescent reporters, to the candidate transcription factors. This makes it much easier to find out who they bind to, where they are localised, and what their levels of expression are – all in the patient derived tumour cells. We can even engineer glioma genes into normal cells to see how they operate, and vice versa – we can try and ‘fix’ the damaged glioma genes in patient’s cells in the dish and see if this brings them back to a normal state. This has created real excitement, and we hope this will help us identify these gene targets much more quickly and effectively.
We’re also, thanks to CRUK funding, able to invest in up-scaling these patient-derived cell lines and use the new genome editing tools to make useful derivatives of these lines. The CRUK Accelerator Award is an infrastructure grant that’s providing us with five years of funding to help us set up these stem cell lines. We’ve linked up with UCL on this, and together have the patient numbers to increase the number and different subtypes and different types of glioma we can include in this open library. The idea is to create an open portal, so researchers can request cell lines, matched molecular data and the associated reporter cells – a glioma cellular genetics resource.
The ultimate goal is of course to improve outlook for patients. My interest remains using the cellular models in the lab for new drug discovery. Ideally we’ll find new agents that will kill the glioblastoma stem cells, but not affect healthy tissue. Current cancer treatments often disrupt all cells in the body to some degree. Our group is interested in identifying tissue specific mechanisms, to reduce the unwanted side effects of damaging other tissues.
A unique opportunity
There is maybe a unique opportunity for brain cancer in targeting stem cell pathways. Unlike tissues such as the gut or blood, where loss of healthy stem cells would be disastrous for the patient, the adult brain doesn’t depend so critically on its stem cells for normal tissue maintenance.
Brain tumours are one of the worst human cancers, with typically awful prognosis. The often late diagnosis, the molecular and genetic heterogeneity of glioblastoma, and issues with delivery of drugs to the brain, all makes it a real challenge to improve survival rates. Also, there have simply not been enough brain tumour researchers in the UK. The investments from CRUK and wealth of new tools that emerge to explore these cancers are going to make a big difference. We need better biological understanding of brain tumours, but also closer interactions with our clinical colleagues to help translate these discoveries into the clinic. That can’t come soon enough.”