Fatty acid metabolism is an essential process in tumor growth and proliferation. Despite different attempts to block fatty acid metabolism as a therapeutic strategy to reduce tumor size and growth, the outcome was not always positive. Now research led by Professor Sarah-Maria Fendt at the VIB-KU Leuven Center for Cancer Biology, working with Professor Leanne Hodson and others at OCDEM, demonstrates that certain tumor cells use an alternative – previously unexplored - pathway to produce fatty acids.
This finding can explain the resistance of particular cancer types to fatty acid metabolism inhibition. It is essential to gain more insights in this process to develop novel therapeutic strategies.
Tumors grow and proliferate, and to do so cancer cells need to duplicate building block molecules. This includes nucleotides to make DNA, but also fatty acids, to make the cell boundaries i.e. the cell membrane.
So unsurprisingly, many cancer cells have upregulated metabolic reactions that lead to increased nucleotide and fatty acid production. Current cancer therapies focus on inhibiting nucleotide and fatty acid generation, to block tumor growth. This strategy is successful for nucleotide metabolism: chemotherapeutic agents such as 5FU and methotrexate inhibit tumor growth by targeting nucleotide generation. But this strategy has had limited success for fatty acid metabolism inhibition.
Researchers at VIB-KU Leuven and OCDEM addressed the question why many cancer cells are resistant to the inhibition of fatty acid metabolism, and particular to the inhibition of the enzyme stearoyl-CoA desaturase (SCD). This enzyme has always been considered to be the only source of newly produced mono-unsaturated fatty acids, which are needed for membrane generation.
The researchers found that some cancer cells instead exploit an unusual metabolic pathway to produce mono-unsaturated fatty acids. This pathway - novel in cancer cells - requires the enzyme fatty acid desaturase (FADS2) and results in the production of the unusual fatty acid sapienate. The research team identified this unusual pathway in isolated cancer cells and in lung (example lung cancer cells pictured: image credit Anne Weston, Francis Crick Institute, via Wellcome Image library) and liver tumors samples from mice and human patients.
Professor Sarah-Maria Fendt (VIB-KU Leuven Center for Cancer Biology) said: “The newly discovered sapienate metabolism constitutes an alternative route for cancer cells to process the fatty acids required for membrane synthesis. These findings can explain the resistance of many cancer types to the inhibition of fatty acid desaturation. Since fatty acids are essential for tumor growth we expect that further dissection of the sapienate metabolism pathway will lead to a better understanding of how cancer cells grow and will thus open new avenues to better target this deadly disease. Moreover, this exciting discovery was supported by a fruitful collaboration between basic scientists and clinicians across three continents.”
(News story adapted from VIB-KU Leuven Centre for Cancer Biology press release.)