New mechanism behind breast cancer metastasis uncovered

Research is teamwork. From left: postdoctoral researcher Kanchan Kumari, research associate Margalida Esteva, associate professor Francesca Aguilo, staff scientist Devi Bhattarai, and  postdoctoral researcher Poonam Baidya.

ImageMattias Pettersson

We discovered that METTL3 has a different function

“We discovered that METTL3 has a different function, which may be just as important for cancer progression as the one previously known,” says Margalida Esteva Socias, research assistant at the Department of Molecular Biology at Umeå University and co–first author of the study.

METTL3 is a well-studied protein that regulates chemical modifications of RNA in the cell. By adding molecular marks to RNA, it helps control which genes are active. Abnormal METTL3 activity has been linked to several types of cancer, and drugs targeting its function are already being tested in clinical trials.

In the new study, the researchers show that METTL3 in breast cancer cells relocates from its usual location in the nucleus to the cytoplasm. There, it becomes part of a transport system that cancer cells use to release molecules into their surroundings.

The researchers found that METTL3 supports this transport system and increases the secretion of proteins that enable cancer cells to invade tissue and spread. When METTL3 was removed, the cells released fewer such proteins, became less invasive, and partly lost their ability to degrade surrounding tissue.

Importantly, these effects could not be reproduced by blocking the protein’s enzymatic activity alone, suggesting that METTL3 also drives cancer through mechanisms other than RNA modification.

The research team also demonstrated that reduced METTL3 levels inhibited tumour growth and delayed the formation of lung metastases.

“Our results indicate that in some cancers, it may not be sufficient to block the enzymatic activity of METTL3. Fully inhibiting its tumor-promoting effects may require strategies that eliminate the entire protein or disrupt its interactions within the cell,” says Francesca Aguilo, associate professor at the Department of Molecular Biology at Umeå University and principal investigator of the study.

The study provides new insights into how cancer cells reshape their environment to invade tissue and spread. The next step is to understand how METTL3 is relocated from the nucleus and whether the same mechanism is involved in other types of cancer.

The study was led by researchers at Umeå University in collaboration with several international partners, including Universitat de Barcelona, Hannover Medical School, and Lund University.

The research was funded by the Knut and Alice Wallenberg Foundation, the Swedish Research Council, Umeå University, the Kempe Foundations, the Cancer Research Foundation in Northern Sweden, and the European Union’s Horizon 2020 programme.