The research, led by CNIO and in which URV researchers participate, has found that the FASN enzyme is crucial for one of the essential processes by which a normal cell becomes cancerous. Blocking this enzyme in an animal model slows the onset of tumours and extends their survival

The body has a process of making fatty acids regulated by the enzyme called FASN. In normal cells, this process is very inactive (except occasionally in the liver and adipose tissue) because most of the fatty acids needed for cell maintenance are obtained externally through the diet.

However, it is known that FASN is overexpressed in many types of cancer, such as prostate, breast, thyroid, colorectal, bladder, lung, and pancreas cancers. Therefore, although its relationship with the disease is still unknown, scientists are studying it as a potential target against cancer. A team of researchers led by Miguel Ángel Quintela, head of the Breast Cancer Clinical Research Unit of the National Centre for Oncological Research (CNIO), has discovered the connection between FASN and cancer and has shown that therapies that inhibit this enzyme are highly effective in the cancer formation phase for preventing the development of tumours in mice and cell cultures; however, it is not effective for treating tumours when they have already appeared. The results have been published in the journal Nature Communications.

One of the main findings is that the importance of FASN to cancer development is not related to its ability to generate fatty acids. Until now, it was thought that tumour cells over-activate the enzyme to generate energy and build their cell membrane. “However, in the study we demonstrate that cancer continues to capture these fatty acids externally,” says Quintela, head of the research project. “Therefore, the function of FASN to synthesize fatty acids is not required for cancer.”

What the cancer does need from this enzyme is that it helps it to arise. Researchers have found that this enzyme is essential for one of the key processes involved in transforming a normal cell into a cancerous cell: anchor-independent growth. This means the cell is able to grow without being attached to a solid surface, a capacity that a normal cell does not have. Among other signs, such as invasion ability, programmed cell death resistance, etc., a vital feature that defines that a cell is transforming into a malignant one is that it can grow autonomously and separate from the tissue it is anchored to. When separated, normal cells undergo a process called anoikis and die, while tumour cells have the ability to continue to grow.

With a transgenic mouse model that develops an aggressive type of breast cancer, the team verified that by eliminating FASN the tumours did not appear. Anchor-independent growth increases the amount of free radicals produced by the mitochondria, which, reaching a point of accumulation, would suffocate cancer cells so they die. How do they avoid this? By using the enzyme. FASN regulates a process called reductive carboxylation that removes this excess of free radicals. That is why when FASN is blocked, free radicals accumulate without stopping, which prevents malignant growth.

At the URV, the researchers Oscar Yanes, Jordi Capellades, Sara Samino and Alexandra Junza, using nuclear magnetic resonance techniques and mass spectrometry with stable isotopes, have helped to demonstrate how FASN regulates reductive carboxylation. By analysing the metabolic fluxes in the presence or absence of this enzyme, the URV team was able to confirm the hypotheses proposed in the research.

The team confirmed these results in normal mouse cell cultures in which they overexpressed known oncogenes, such as KRAS (related to lung cancer) and PYMT and HER2 (related to breast cancer), to induce the transformation of normal cells into tumour cells. By eliminating FASN expression, normal cells did not transform into tumour cells, even though the oncogenes were overexpressed.

Preventive efficacy

Researchers around the world are examining the potential of FASN to treat certain types of cancer. However, the results indicate that its effectiveness is preventive, not therapeutic. In the mouse model of highly penetrating breast cancer, the areas where FASN is located did indeed develop cancer, whereas in those areas where it is blocked, no tumours were generated and survival increased by 68%. “But when we tried to inhibit FASN when the tumours are already established, there was a small transient effect that affected the progress of the disease very little,” says the head researcher.

In the next steps of the research, the team will study the implications of these findings for metastasis and for the immune system’s response to tumours. In the future, the potential of the finding for possible application in at-risk populations could also be analysed.

Bibliographic reference: Essentiality of fatty acid synthase in the 2D to anchorage-independent growth transition in transforming cells. Maria J. Bueno et al (Nature Communications, 2019). DOI: 10.1038/s41467-019-13028-1