Ribosomopathies—congenital disorders involving mutations in the structure or function of ribosomal component proteins or their assembly factors—are initially characterized by the underproduction of cells. Yet many ribosomopathies later put individuals at risk for cancers involving the overproliferation of cells. How can this be?
"Defects in ribosomes have two different consequences for the cells," explained Kim De Keersmaecker, PhD, Head of the Laboratory for Disease Mechanisms in Cancer in Leuven, Belgium, and senior author of a study that provides answers to this longstanding mystery. "On the one hand, the defective ribosomes make specific kinds of mistakes which leads to the increased production of the proteins that nourish cancer cells. At the same time, these ribosome defects cause a build-up of toxic substances that damage the cells, forcing them to grow and divide less. The cell suffers from several different kinds of damage, including DNA damage. This in turn causes mutations."
In addition to the cancer risk associated with ribosomopathies, ribosomal protein (RP) mutations passed on in the course of cell division are now known to be involved in various cancers. The recurrent RPL10-R98S mutation is implicated in T-cell acute lymphoblastic leukemia (T-ALL), and RPS15 mutations are linked to chronic lymphocytic leukemia (CLL).
In prior investigations, the researchers at the Laboratory for Disease Mechanisms in Cancer demonstrated that RPL10-R98S both enhances the expression of oncogenes and causes a defect in proliferation as a result of elevated oxidative stress. In their latest study, recently published in Cancer Research, Dr. Keersmaecker's team has shown that RPL10-R98S mouse lymphoid cells compensate for the proliferation defect caused by the RPL10-R98S mutation by acquiring five times more secondary mutations than RPL10 wild-type cells do.
"All these mutations will eventually include one that is able to compensate for the cell damage and 'rescue' the cell, allowing cell division to increase. At that point, cancer cells can take advantage of the high availability of proteins that favor their growth," explained Dr. Keersmaecker. "This opens the floodgates, with ever-increasing cancer protein levels and even better 'rescuing' mutations protecting cells from damage. This allows a tumor to grow in an uncontrolled way."
In patients with T-ALL, the occurrence of RPL10-R98S and other RP mutations was associated with a greater mutational burden and enrichment in lesions that activate NOTCH1, which promotes cancer in T-ALL. The oxidative stress induced by RPL10-R98S led to DNA damage and restricted cellular growth. However, NOTCH1 expression eliminated these effects in RPL10-R98S cells without affecting RPL10 wild-type cells. One way in which NOTCH1 expression eliminated the DNA damage and restricted cellular growth in RPL10-R98S cells was by reducing the expression of protein kinase C (PKC)-θ, which plays a role in the signal transduction of the immune system's T cells.
In patients with CLL, the researchers also found that RP mutations were associated with a greater mutational load, including mutations capable of reducing oxidative stress.
Dr. Keersmaecker emphasized the broader applicability of her team's results: "We see these defects both in congenital and non-congenital cancers. And now we also know that ribosome defects can give rise to a whole series of additional cellular defects. In other words, if we can tackle the cause, we can prevent many of the downstream problems. This is the research track we are currently exploring."
For More Information
Sulima SO, Kampen KR, Vereecke S, et al (2018). Ribosomal lesions promote oncogenic mutagenesis. Cancer Res. [Epub ahead of print] DOI:10.1158/0008-5472.CAN-18-1987
Image courtesy of Furfur.