While most of us wouldn’t want our cells sucking up more fat, cancer cells often need to adjust their metabolic needs to compensate for a deficiency in the production of certain lipid molecules. Now, a team of scientists from the University of Toronto has utilized genome-wide CRISPR screens to investigate global changes in cancerous cells as they adapt to a shortfall of critical nutrients such as lipids, which make up the cell’s outer membrane. When cancer cells are unable to make their own lipids, they gobble them up from their environment to ensure a steady supply of these essential building blocks, the study found. Lipids also serve as fuel and chemical signals for communication between cells, among other roles.
Understanding these underlying metabolic mechanisms could help investigators prevent the likelihood of it becoming resistant to treatment.
“Several clinical trials have failed because metabolism is such an adaptive process by which cancer cells gain drug resistance,” explained co-lead study investigator Michael Aregger, PhD, a research associate at the Donnelly Centre for Cellular and Biomolecular Research at the University of Toronto. “If you know how cells are able to adapt to perturbations, maybe we can target them more specifically to avoid resistance from developing.”
Findings from the new study published recently in Nature Metabolism through an article titled, “Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism.”
The switch in metabolism could be bad news for drugmakers seeking to target cancer by reducing its lipid reserves. In particular, drugs that inhibit an enzyme called FASN, for fatty acid synthase, involved in an early step of lipid synthesis, are being explored in patient trials. Fatty acids are precursors of larger lipid molecules, and their production is increased in many cancers thanks to elevated FASN levels, which are also associated with poor patient prognosis.
The current study suggests that the effectiveness of FASN inhibitors could be short-lived owing to cancer’s ability to find another way to procure lipids.
“Because FASN is upregulated in many cancers, fatty acid synthesis is one of the most promising metabolic pathways to target,” noted co-lead study investigator Keith Lawson, a PhD student enrolled in the surgeon-scientist program at the University of Toronto. “Given that we know there is a lot of plasticity in metabolic processes, we wanted to identify and predict ways in which cancer cells can potentially overcome the inhibition of lipid synthesis.”
To block fatty acid synthesis, the researchers employed a human cell line from which the FASN coding gene was removed. Using the genome-editing tool CRISPR, they deleted from these cells all ~18,000 or so human genes, one by one, to find those that can compensate for the halt in lipid production. Such functional relationships are also referred to as “genetic interactions.”
“We use pooled genome-wide CRISPR screens to systematically map genetic interactions (GIs) in human HAP1 cells carrying a loss-of-function mutation in fatty acid synthase (FASN), whose product catalyzes the formation of long-chain fatty acids,” the authors wrote. “FASN-mutant cells show a strong dependence on lipid uptake that is reflected in negative GIs with genes involved in the LDL receptor pathway, vesicle trafficking, and protein glycosylation. Further support for these functional relationships is derived from additional GI screens in query cell lines deficient in other genes involved in lipid metabolism, including LDLR, SREBF1, SREBF2, and ACACA. Our GI profiles also identify a potential role for the previously uncharacterized gene C12orf49 (which we call LUR1) in the regulation of exogenous lipid uptake through modulation of SREBF2 signaling in response to lipid starvation.”
Data analysis revealed hundreds of genes that become essential when cells are starved of fat. Their protein products clustered into well-known metabolic pathways through which cells hoover up dietary cholesterol and other lipids from their surroundings.
The cells’ intake of cholesterol has become textbook knowledge since it was discovered half a century ago, winning a Nobel Prize and inspiring the blockbuster drug statin and many others. But the new study found that one component of this process remained overlooked all this time. The gene encoding it was only known as C12orf49, named after its location on chromosome 12. The researchers re-named the gene LUR1, for lipid uptake regulator 1, and showed that it helps switch on a set of genes directly involved in lipid import.
“This was a big surprise to us that we were able to identify a new component of the process we thought we knew everything about,” Aregger remarked. “It really highlights the power of our global genetic interaction approach that allowed us to identify a new player in lipid uptake in a completely unbiased way.”
Amazingly, two additional groups working independently in New York and Amsterdam also linked C12orf49 to lipid metabolism, lending further support for the gene’s role in this process.
Inhibiting LUR1 or other components of lipid import, along with FASN, could lead to more effective cancer treatments. Such combination therapies are thought to be less susceptible to emerging drug resistance because the cells would have to simultaneously overcome two obstacles—blocked lipid production and import—which has a lower probability of occurring.
“Therapeutic context that comes out of our work is that you should be targeting lipid uptake in addition to targeting lipid synthesis, and our work highlights some specific genes that could be candidates,” Lawson concluded.
