Understanding and exploiting ribosome biogenesis dysregulation in cancer

Background: Ribosome biogenesis is a highly complex and metabolically demanding process that is essential for protein synthesis in all cells. In normal cells, ribosome biogenesis is under tight regulation. However, this process often becomes dysregulated in cancer.

Such dysregulation is now recognised as a hallmark of most malignancies, but the detailed molecular mechanisms behind it remain poorly understood.

Aims: Our proposed programme aims to tackle this challenge in a systematic manner, by uncovering the basis for the malignant dysregulation of ribosome biogenesis at different molecular levels, with a particular focus on identifying cancer-specific vulnerabilities that could be therapeutically exploited.

Methods: Our programme consists of 3 distinct but interconnected work-packages (WPs): WP1- Understanding oncogene-induced reconfiguration of the nucleolus: We will determine how the molecular composition of the nucleolus, the primary cellular sites of ribosome biogenesis, changes during malignancy, and how such changes affect ribosomal-RNA (rRNA) synthesis and processing.

We will also assess the impact of such changes on tumourigenesis, revealing potential therapeutic opportunities.

WP2: Characterising oncogenic alterations in the pre-rRNA interactome: We will utilise our newly developed TREX technique to unbiasedly identify pre-rRNA interactions that change upon oncogenic transformation, and assess their impacts on ribosome biogenesis and tumourigenesis. We will identify cancer-specific vulnerabilities and potential therapeutic targets.

WP3: Elucidating the oncogene-driven synthesis of ribosomal-proteins (RPs): We will elucidate how RP synthesis is up-regulated during malignancy to support enhanced ribosome biogenesis, and assess the impact of this process on tumourigenesis. We will then investigate how this process may be targeted, alone or in combination, through detailed analyses.

How the results will be used: The results of this research will advance our understanding of ribosome biogenesis and its dysregulation in cancer, leading to the identification of novel therapeutic targets.

Ribosomes are among the most prominent drug targets in biology (e.g. many eukaryotic/prokaryotic antibiotics), owing to their essential functions.

In the context of cancer treatment, it is now clear that several existing chemotherapies function by targeting ribosome synthesis. However,existing drugs cannot differentiate between cancerous and normal proliferative cells.

Therefore, identification of strategies to specifically target ribosome synthesis in cancer cells has immense therapeutic promise. The immediate beneficiaries of our work will be other researchers in related fields (e.g.

Ribosome, RNA, & Cancer Biology), but our findings may also have significant implications for translational researchers in academia and industry, who are focused in developing novel cancer therapies, thus benefiting cancer patients in the long run.