Investigating the role of fatty acids in cancer cell survival

Northwestern Medicine researchers have found that a specific enzyme is required to regulate cancer cell survival and metastasis under cellular stress, findings published in Proceedings of the National Academy of Sciences.

The study, led by Daniela Mattei, MD, Diana Princess of Wales Cancer Research Professor and Head of Reproductive Science in Medicine in the Department of Obstetrics and Gynecology, also suggests that targeting this enzyme in combination with dietary interventions may be a promising strategy cancer treatment.

Fatty acids, or lipids, act as an alternative energy source for cancer cells when glucose and oxygen are limited in the tumor microenvironment. To maintain proper intracellular functioning, including cell signaling and lipid storage, saturated fatty acids turn into unsaturated fatty acids by an enzyme called stearoylCo-A desaturase (SCD). This “desaturation” is the final step in lipogenesis, the process of converting metabolites into fatty acids and energy.

Although SCD is known to be essential for maintaining lipid balance in cancer cells, how it affects cancer cell survival and tumor progression remains poorly understood. However, previous work from Matei’s lab showed that cancer stem cells are enriched in unsaturated fatty acids and that targeting SCD eliminates cancer stem cells.

Taking their findings one step further in the current study, the researchers used transcriptomics, lipidomics, and single-cell imaging to reveal how SCD fatty acid regulation affects ovarian cancer cell survival.

They found that inhibiting or depleting SCD completely reduced the amount of unsaturated fatty acids in cancer cells, tipping the balance toward saturated fatty acids. On the contrary, increased levels of unsaturated fatty acids protect against cancer cells cellular stress provoked by Endoplasmic reticulum (ER), a network of tubules in the cytoplasm that transports proteins and lipids throughout the cell.

“The balance between saturated and unsaturated fatty acids is very important to maintain the integrity of the endoplasmic reticulum. So, if there are too many saturated fatty acids, the cell will die, but the unsaturated fatty acids act as a buffer,” said Matej. , who is also a professor of medicine in the division of hematology and oncology and a member of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.

Then, using xenograft models of ovarian cancer, the researchers found that inhibiting SCD blocked tumor growth in vivo. Furthermore, combining an SCD inhibitor with a diet enriched in saturated fatty acids in in vivo models of ovarian cancer initiated the ER stress response and prevented tumor progression.

The findings show that SCD is a key regulator of cancer cell fate metabolic stress and that is aimed at the balance of lipids in cancer cells may be an effective therapeutic strategy, according to the authors.

“Given the plasticity and redundancy of metabolic pathways that have largely thwarted previous attempts to use metabolic interventions to treat cancer, our results highlight the importance of combination strategies,” said Guanyuan Zhao, a Driskill graduate student in life sciences. (DGP) and lead author of the study.