Three of the researchers behind the study, Kanchan Kumari Francesca Aguilo Margalida Esteva, Department of Molecular Biology.
Photo Credit: Mattias Pettersson
Scientific Frontline: "At a Glance" Summary
- Discovery: Researchers at Umeå University identified a novel mechanism in triple-negative breast cancer wherein the enzyme fibrillarin fine-tunes protein production to facilitate tumor growth and adaptation.
- Mechanism: Fibrillarin regulates the 2′-O-methylation (Nm) of ribosomal RNA and collaborates with the ribosomal protein RPS28 to construct specialized ribosomes with distinct translational capabilities.
- Specific Consequence: The depletion of fibrillarin causes a concurrent loss of RPS28, resulting in ribosomal heterogeneity—an imbalance of ribosome types that alters the proteome and drives oncogenic development.
- Context: This research shifts the understanding of cancer etiology beyond solely genetic mutations to include translational control, demonstrating how aggressive cells manipulate protein synthesis machinery.
- Implication: The findings suggest that targeting the ribosome assembly and modification machinery could serve as a new therapeutic strategy for treating aggressive cancers defined by misregulated protein production.
A previously unknown mechanism that makes it possible for aggressive so-called triple-negative breast cancer to fine-tune its production of proteins has been discovered by researchers at Umeå University, Sweden. The discovery increases our understanding of how tumors grow and adapt, and it opens up for research into new future treatments.
"We have found a critical control point that, when disturbed, can tip the balance against cancer," says Francesca Aguilo, associate professor at the Department of Molecular Biology at Umeå University and who has led the current study.
All cells in the body use ribosomes, small molecular factories, to translate genetic information from RNA into proteins. Ribosomes are complex structures made up of ribosomal RNA and proteins, and they have built-in control systems that ensure that everything works as it should. When these systems are disrupted, diseases such as cancer can occur.
Ribosomal RNA is rich in chemical modifications that help the ribosome function optimally. One such modification is 2′-O-methylation, Nm, which is controlled by the enzyme fibrillarin. The new study shows that fibrillarin plays a key role in how ribosomes are built and which proteins are made.
The researchers discovered that fibrillarin collaborates with the ribosome protein RPS28 to create specialized ribosomes with unique properties. When fibrillarin is missing, RPS28 also disappears, leading to a mixture of different ribosome types – so-called ribosomal heterogeneity. This imbalance affects which proteins are produced and can drive the development of cancer.
"Cancer is not only about mutated genes, but also about how cells control the amount and type of proteins that are produced," says Francesca Aguilo.
Although more research is needed before the results can be translated into treatments, the study points to a new direction for research on treatments; to attack cancer as a disease of misregulated protein production.
Funding: Swedish Research Council, the Swedish Cancer Society and the Knut and Alice Wallenberg and Kempe Foundations, among others
Published in journal: Cancer Letters
Authors: Paula Groza, Kanchan Kumari, Margalida Esteva-Socias, Johanna Schott, Devi Prasad Bhattarai, Joanna J Sajkowska, Rubin Dasgupta, Carlos Peula, Eliana Destefanis, Chloe Williams, Virginie Marchand, Pernilla Wikström, Rebecca Wiberg, Ana Bosch Campos, Jonathan D Gilthorpe, Bogdan Pop, Andre Mateus, Yuri Motorin, Erik Dassi, Katja Petzold, Francesca Tuorto, and Francesca Aguilo
Source/Credit: Umeå University | Ola Nilsson
Reference Number: ongy011226_01
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