Ribosomes are amongst the most common natural drug targets, a feature reflective of their critical function in underpinning all aspects of life. Most classes of antibiotics currently in clinical use, for example, target ribosomes in specific bacteria.

For a long time, the idea that this could be utilised in cancer was thought to be impossible. Cancer cells and their normal counterparts share a common type of ribosome – unlike bacteria and human cells. However, this view has begun to shift in recent years.

In human cells, ribosome biogenesis, begins in the nucleolus. Here, large precursor ribosomal RNA molecules – which eventually form the core of ribosomes – are generated, carefully cut, folded, and assembled into the maturing ribosomal subunits along with dozens of ribosomal proteins. These maturing subunits then exit the nucleolus and nucleus, and enter the cytoplasm, where the last remaining maturation steps take place, leading to fully functional ribosomal subunits capable of carrying out protein synthesis. The entire process of ribosome biogenesis involves hundreds of molecular players, acting in a precisely choreographed manner to produce functional ribosomes.

In addition to being complex, ribosome biogenesis is amongst the most energy-intensive processes in our cells, with some estimates suggesting that more than 60% of all the ATP generated in a rapidly proliferating cell is consumed for ribosome production. It is therefore not surprising that this process is found to be under tight regulation to ensure ribosomes are only made when they are needed. However, this tight regulation seems to become universally corrupted in cancer, with malignant cells often ramping up ribosome production in a seemingly uncontrollable fashion, in order to meet their insatiable demands for higher protein synthesis. One striking side-effect of this upregulation is the enlarged nucleoli, often observed specifically in tumour cells, which pathologists have been using for over a century for cancer diagnosis.

A double-edged sword

But recent studies suggest that whilst uncontrolled ribosome production gives tumour cells a growth advantage, it may also make them vulnerable in specific ways.

For example, it is now known that imbalances in the process of ribosome biogenesis (which can be the result of their ramped up uncontrolled synthesis), can trigger the activation of the p53 master tumour suppressor. This can, of course, put the brakes on cell division or even push a cell into self-destruction via apoptosis. Many chemotherapies already work, at least in part, by disrupting ribosome production in cancer cells and triggering this p53-dependent response, although management of the side-effects of these pleotropic agents makes them less than ideal for specifically exploiting this vulnerability in cancer cells.

Rapid production may also lead to errors and omissions in certain parts of the ribosome, rendering the resulting cancer ribosomes somewhat different from their normal counterparts. The real challenge (and opportunity) is to reveal the exact molecular details of ribosome alterations in cancer cells, in order to find ways to selectively target the production or function of the resulting cancer ribosomes, without harming their normal counterparts in healthy tissues.

A new therapeutic frontier

Now, a number of research groups, including ours, have set out to decode how ribosomes and their biogenesis are molecularly rewired in cancer.

More importantly, we are keen to find out how we might exploit such changes for therapeutic purposes. If successful, these therapies could be game-changing, due to the ubiquitously critical nature of the role ribosomes play in supporting cancer cell survival and proliferation. My team is focusing specifically on pancreatic cancer, one of the most lethal cancers, where nearly all patients have mutations in the cancer driver gene KRAS. Our previous research has shown that KRAS mutations acts as a molecular accelerator pedal, ramping up the production ribosomes in ways that we are only beginning to understand.

Our lab is keen to use a novel technique called TREX, which we have recently developed, in order to map in detail how each region of ribosomal RNAs interacts with ribosomal proteins and processing factors throughout the life-cycle of ribosome. We can also explore how these interactions change upon introduction of oncogenic KRAS mutations, leading to alteration in the molecular wiring of ribosome biogenesis, or in certain cases, generating different ribosomes.

Using various in vitro biochemical tools and in vivo animal models, we then aim to understand whether these changes can bring about unique vulnerabilities that can be therapeutically exploited for targeting pancreatic cancer.

As cancer researchers, we are beginning to see ribosomes not just as highly conserved and invariant cellular machines that carry out the essential task of protein synthesis, but as a rich and underexplored landscape of therapeutic opportunity. By uncovering how cancer cells hijack and reprogram the machinery of ribosome biogenesis to fuel their growth, we may be able to develop a new generation of anti-cancer therapies aimed at targeting cancer ribosomes, which are both highly specific and broadly applicable.

So can ribosome biogenesis, a fundamental driver of tumour growth, be turned into an Achilles’ heel for cancer? We believe it just might…