EACR 2016
Polycomb repressors and epigenetic therapy
Dr Maarten van Lohuizen - Netherlands Cancer Institute, Netherlands, UK
I work on transcriptional repressive complexes, so that’s a difficult word for protein complexes that shed off genes. They have been first discovered in Drosophila, hence their name polycomb complexes, so it’s a very fundamental process. What they do is actually they regulate what we call cell fate so they determine whether a liver cell is a liver cell or a brain cell is a brain cell. So that’s a very fundamental process and maybe not surprisingly what we have discovered in the past and have been studying ever since is that these complexes when deregulated are implicated not in just one form of cancer but in multiple forms of cancer.
Does this mean cancer is taking a step back in terms of development?
You can say that. So some of these complexes that we’ve discovered in fact stabilise what we call stem cell fates, so primitive cell fates. When a cell differentiates in normal development those complexes should be changed into complexes that now stabilise more differentiated cell fates and that process goes awry in cancer. Indeed, it’s a case that what we often see in cancer is now the more stem cell-like complexes are aberrantly upregulated, indeed making a cell more primitive and more stem cell-like and that’s a step on the way to a cancer cell.
Do you see this protein dysregulation in developmental diseases?
Also, and this is how these polycomb complexes have first been discovered in Drosophila, in the fruit fly, when you mutate them there’s also consequences for development because, as I was explaining, they determine cell fate. So if you mess up with these protein complexes not only can cancer develop but also development goes wrong and so there’s many developmental abnormalities if these processes are deregulated as well.
What sort of methods do you use in your lab?
We use a large range of methods. So these protein complexes work at gene regulation, so at the level of what we call chromatin DNA in the nucleus. So we study that using cell-based assays and biochemistry but we also go all the way to cancer models, preclinical cancer models, and even human cancer to study the consequences of deregulation of these complexes and whether we can, in fact, use that information to find new therapies. That’s something we’re also very active in.
What clinical benefits have you seen?
What we’ve discovered, and this is exactly what I also discussed here at the meeting, is our recent work that just got published in Cancer Cell where we showed that in, for instance, lung cancer there’s two groups of patients and this is how this work started. So we discovered that in lung cancer one group of patients have more of these protein complexes suggesting that they would be acting maybe as oncogenes, so genes that when overexpressed cause cancer, but there was also another subgroup of patients in this heterogeneous lung cancer disease that has the opposite, so where these complexes were actually completely shut off suggesting that when these complexes are gone they promote tumour genesis. We wanted to understand why this is and that is what we actually discovered in that paper, how that molecularly works. So it turns out that it is context dependent, and this is a recurring theme now in cancer where we find this more often for such important widespread regulators, that on the one hand, depending on the other mutations that are there in the cancer, they can act as oncogenes, so genes that when overexpressed promote cancer. On the other hand, in other contexts, loss of polycomb function is required for the cancer to develop.
Where do you see your research going in the future?
What we really would want is to understand better these different contexts that I was referring to because cancers are, of course, different and for different cancers we now know that we have to dive very deep to understand also the molecular basis because when these factors act as oncogenes then, of course, there would be a lot of interest, and there is a lot of interest, from the pharmaceutical industry to make inhibitors against the enzymes in these complexes because, as I said, it’s very broad, it’s not just for lung cancer, it’s in many different cancers that we find that. But in the other context, when you inhibit these complexes and they would promote cancer in the other context, that would be dangerous. So you really need to understand exactly what you are investigating there and what the consequences are of all the mutations in cancer. So there we really also can use our mouse models to investigate this and to come up, hopefully, with new combinations of therapy that would be working in specific subsets of cancer patients that have to be pre-selected based on the mutations that they carry.
