New cancer target: fatty acids need to be synthesized for brain metastasis

Breaking new ground 5. jun 2021 2 min Postdoc Raphael Ferreira Written by Kristian Sjøgren

Breast cancer often metastasizes, and when this reaches the brain, the survival outlook is poor. New research shows a new way to prevent cancer from attacking the brain.

People with human epidermal growth factor receptor 2 (HER2)-positive breast cancer have few treatment options, and they have a high risk of metastasis, including into the brain. These people have an extremely poor prognosis, and the blood–brain barrier prevents drugs from reaching the brain.

However, good news may be on the way since researchers have figured out that growing cancer cells need to increase the production of fatty acids in the brain by boosting the relevant cellular machinery.

This discovery opens up a potential therapeutic target for combatting a deadly disease.

“This study aimed to understand what happens in the brain when the cancer metastasizes and what the cancer cells require to survive and spread. We found that the cancer cells upregulate the genes that control the synthesis of fatty acids in the brain, and limiting this ability to produce more fatty acids may enable us to inhibit their growth or kill them,” explains co-author Raphael Ferreira, Postdoctoral Fellow, Harvard Medical School, Boston, United States.

Gino B. Ferraro, Ahmed Ali and Alba Luengo are the first authors, and the study has been published in Nature Cancer.

Cancer cells boost the production of fatty acids

The researchers investigated the genetic expression of breast cancer cells, metastatic cancer cells in the brain and cells in healthy tissue by using mice. They also verified their results in samples from people. The genes controlling fatty acid synthesis were overexpressed in the metastatic cancer cells in the brain compared with breast cancer cells.

Fatty acids are an essential part of the structure of all cells, and cancer cells require lots of fatty acids since they grow much faster than normal cells.

Raphael Ferreira explains that cancer cells are extremely adaptable, and the brain has many fewer fatty acids available than breast tissue. The cancer cells therefore upregulate the relevant genes to accelerate their growth.

“Cancer cells are extremely good at utilizing the available nutrients. The brain lacks fatty acids, which causes the cancer cells to overexpress the genes for fatty acid synthesis, thereby enabling access to the fatty acids required to maintain rapid growth,” says Raphael Ferreira.

Stopping cancer from metastasizing

The discovery leads to interesting therapeutic perspectives, which the researchers also examined by genetically inhibiting the fatty acid synthesis in the brains of mice with metastasized breast cancer. This prevented the cancer cells circulating in the bloodstream from metastasizing into the brain, enabling the mice to survive longer.

In another experiment, the researchers gave the mice commercially available substances that can penetrate the blood–brain barrier and inhibit fatty acid synthesis. This reduced synthesis but not as effectively as manipulating genes.

“This proof-of-concept study shows that fatty acid synthesis can be inhibited and thus prevent HER2-positive breast cancer from metastasizing into the brain. The next step is to find substances that can more easily penetrate the blood–brain barrier and effectively inhibit synthesis,” explains Raphael Ferreira.

Aiming for the Achilles’ heel

Raphael Ferreira says that the discovery is relevant for other purposes than understanding the importance of fatty acids for HER2-positive breast cancer metastasis.

The results provide greater insight into the importance of the microenvironment for cancer and how this knowledge can be used to aim for the Achilles’ heel of different types of cancer.

“We show that fatty acid synthesis is crucial for metastatic cancer in the brain, but this may differ for other types of cancer and metastasis in other organs. The aim is to identify the weaknesses of different types of cancer and then attack these vulnerabilities,” says Raphael Ferreira.

Fatty acid synthesis is required for breast cancer brain metastasis” has been published in Nature Cancer. Raphael Ferreira is associated with the Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, which is supported by the Novo Nordisk Foundation.

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