Biochemistry

Researchers now demonstrate 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. 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.
Researchers from the lab of Prof. Sarah-Maria Fendt at the VIB-KU Leuven Center for Cancer Biology now demonstrate 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. The results are published in the journal Nature.

Inhibition of nucleotide and fatty acid

Tumors grow and proliferate, and to do so cancer cells require the duplication of building block molecules. This includes nucleotides to make DNA, but also fatty acids to make the cell boundaries i.e. the cell membrane. Not surprisingly, many cancer cells have upregulated metabolic reactions that lead to increased nucleotide and fatty acid production. Current developed therapies focus on the inhibition of nucleotide and fatty acid generation to block tumor growth.

This strategy has proven to be successful in the case of nucleotide metabolism: chemotherapeutic agents currently used in cancer treatment such as 5FU and methotrexate inhibit tumor growth by targeting nucleotide generation. Surprisingly however, this effort had limited success for fatty acid metabolism inhibition. Kim Vriens, Stefan Christen and colleagues in the lab of Sarah-Maria Fendt (VIB-KU Leuven) 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).

Sapienate metabolism: an alternative route for cancer cells

This enzyme is the only source of; new mono-unsaturated fatty acids; which we need for membrane generation. However, the researchers now found that some cancer cells exploit a 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 presence of this novel and alternative metabolic pathway had identity in isolated cancer cells and in lung and liver tumors samples from mice and human patients.

Prof. Sarah-Maria Fendt 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 had support by a fruitful collaboration between basic scientists and clinicians across three continents.”