For a long time, cancer was thought to be a sort of random event and it was not clear that the etiology of cancer was associated with changes in the genes.

One particularly important set of signals, the endocrine signals – the typical oestrogen and androgen signals – are responsible, for instance, for breast cancer and prostate cancer in men and women. So, interactions of broken genes and signals from outside of the cells really creates the prerequisite for the cancer cell to develop, differentiate and grow and to start accumulating even more mutations. There’s also a very precise set of steps the cancer goes through because the initial mutation is almost never tumorigenic. So, even in the most powerful oncogene, a gene called KRAS, it’s not sufficient to have a mutation because the cell already knows that if you have a mutation in KRAS, you’ve got to stop everything you’re doing and put that cell into a senescent state so that it will no longer be a problem. Recently, in our nevi, we have a lot of mutations in KRAS or BRAF that are not tumorigenic, because they’re kept at bay by senescence. You need not just one gene, but many genes, to be broken and so, typically, the combination is an oncogene and a tumour suppressor.

This is basically the foundation of cancer. Now that we have discovered that the individual genes don’t really tell us the full story – and there are many patients with cancer where we can’t even find what we call a driver mutation – and that there has to be something more complex, which is exactly what we’re looking for, for instance in looking at the dysregulation of transcription, we find that the transcription factors and cofactors that are dysregulated in cancer that are acting in an abnormal way in cancer cells are extremely more conserved and reproducible than the specific mutations that induce the cancer state. This is why, in our lab, we are focusing much more on developing treatments that will target these transcription factor activities as opposed to targeting genes that are broken by mutations.

We thought until very recently of cancer as sort of a monolithic object, where the cells of the cancer cell are all doing the same thing – and all doing the same wrong thing. It turns out that that’s not the case. Cancers have cells that are in multiple states. Think of those states as being the three primary colours on a palette. You can then generate any colour you want by simply mixing those colours in different ratios. What happens is that cancers have looked very different in many cases because they have had these primary colours that form them mixed together in very different ratios within each individual. And so, the individuals look different from another one while the actual primary state of the cancer cells is exactly the same. This is a very important concept because what we find is that, even after treatment with drugs, the cancer cells are not really changed, overall. If you look at the entire tumour and you average across all the cells, the tumour will look very different. It’s simply because within the same patient, the ratios between the populations of cells that are in one state versus another have changed.

This tells us that if we actually find recipes to effectively target those primary cell populations, then we could actually deal with any tumour. Now, this is within one patient. When you extrapolate this concept to all the patients with different cancers, what emerged from a recent analysis that was just published in Cell is that we could only find 24 major modules of master regulators. Remember, these are the proteins that control the expression of the genetic programmes that make the cell work in a certain way or another. These 24 blocks were turned on and off in different ways, in different tumours, but they were pretty much exactly the same blocks and pretty much working in the same way in different tumours. It’s a bit like a Lego recipe, where you have different pieces. But these pieces could only be assembled to 24 different types of pieces in different ways.