New research reveals a previously unknown plasticity in the lipid metabolism of some tumor types. Instead of relying on the canonical SCD pathway for fatty-acid desaturation, the cells exploit a different enzyme, FADS2, and upregulate this alternative route when SCD is inhibited.

Recent findings from researchers at the VIB-KU Leuven Center for Cancer Biology in Belgium indicate that some tumor cells can exploit a hitherto little-known pathway to supply themselves with fatty acids for proliferation (Nature 2019;566:403–6). This may help explain why therapeutic efforts targeting lipid metabolism, in the context of cancer, have been largely unsuccessful so far.

Tumor cells often have aberrantly activated metabolic processes, including increased nucleotide generation and fatty-acid production, explains senior author Sarah-Maria Fendt, PhD. However, whereas the former can be effectively inhibited with chemotherapy, blocking the latter has proven much trickier.

Until recently, Fendt says, the enzyme stearoyl-CoA desaturase (SCD) was widely regarded as the primary driver of a catalytic reaction that desaturates the fatty acids palmitate and stearate via the formation of a specific double bond, thereby generating palmitoleate and oleate—important components of cellular membranes. As such, “inhibiting this canonical pathway should kill cancer cells” with overly active fatty-acid desaturation, she says, yet attempts to develop SCD inhibitors have, to date, stalled at the preclinical stage due to “very mixed efficacy seen in early studies.”

When the researchers tested one such agent in a panel of cancer cell lines, they saw that “some cells were clearly dependent on SCD and stopped proliferating altogether, but others didn't appear to be affected,” Fendt says. Wondering whether an alternative fatty-acid synthesis route might be involved, “we reasoned that if so, SCD-independent cancer cells probably contained some unusual fatty acids,” she adds. Metabolomic analyses showed that this was indeed the case, with one fatty acid, sapienate, standing out: “The more sapienate in cancer cells, the stronger their resistance to SCD inhibition,” Fendt notes.

Aware that sapienate, a key component of human sebum, is produced in sebocytes by fatty acid desaturase 2 (FADS2), the team decided to see if this enzyme was also exploited by tumor cells. They observed that liver and lung cancer cells, which were SCD-independent, had elevated FADS2 expression compared with that of SCD-dependent breast cancer cells. Both in vitro and in vivo, silencing FADS2 led to reduced sapienate production; on the other hand, overexpressing FADS2 in SCD-dependent tumor cells restored their ability to proliferate even when SCD was inhibited. Dual inhibition of FADS2 and SCD, however, significantly reduced tumor growth in a mouse model of human liver cancer that was unresponsive to SCD blockade alone.

Next, the researchers determined that sapienate and its downstream metabolite, cis-8-octadecenoate, could be incorporated into the membrane lipids of tumor cells. This finding intrigues Andrew Hoy, PhD, head of the University of Sydney's Lipid Metabolism Laboratory in Australia. “What advantage it may provide cancer cells, if any, remains to be identified,” he says.

Fendt notes that “FADS2 signaling doesn't come into play solely upon SCD inhibition. We saw baseline activity of both pathways in our cancer cells—it's just that in some, FADS2 really spiked when SCD was blocked.” She and Hoy now wonder why such alternative upregulation occurs only in certain tumor types, and what additional benefits it may offer. One hypothesis is that sapienate and other atypical FADS2-derived metabolites could help the cells influence and deregulate broader lipid signaling networks. It's one of many facets of this newly identified metabolic plasticity that Fendt and her team plan to explore, hoping to find “clues for better therapeutic options, including combination strategies, down the road.”

Overall, “this discovery provides exciting new insight into the synthesis of fatty acids by cancer cells,” Hoy says. “It promotes the notion that there is diversity at work here, adding to what's been found for glucose and amino acid metabolism.” –Alissa Poh

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.