Hungarian researchers identify a switch that inhibits tumour growth – revealing the link between the tumour’s own fatty-acid production and cell-growth signalling

The Molecular Tumour Biology and Autophagy Research Group at the Faculty of Science of Eötvös Loránd University (ELTE), working in collaboration with researchers from the HUN-REN Biological Research Centre in Szeged, investigated this question. Their findings were published in Cell Death & Disease.

Without the ACC enzyme, tumours cannot enter a rapid-growth phase

The research group, led by Szabolcs Takáts, conducted functional genetic studies using tumour models generated in the developing eye of the fruit fly (Drosophila melanogaster). This model makes it possible to track the roles of individual metabolic processes in tumour development in a living organism using targeted genetic interventions.

The researchers inhibited the function of enzymes involved in the production of neutral lipids and fatty acids and then examined how the resulting loss of function affected tumour growth. They found that ACC, or acetyl-CoA carboxylase, which catalyses the first key step in fatty-acid synthesis, is essential for a tumour to enter the late, rapid-growth phase. In the absence of ACC, tumour growth slowed markedly.

The types of fatty acids incorporated into lipids matter

To determine what happens to lipid metabolism in tumour cells when ACC function is lost, the research group carried out detailed lipidomic analyses with Mária Péter and Gábor Balogh of the HUN-REN Biological Research Centre. Lipidomics enables the comprehensive analysis of the composition of lipid molecules found in cells and tissues.

In the absence of ACC, the lipid composition of the tumours changed substantially: the amount of fatty acids derived from de novo synthesis decreased, while the proportion of polyunsaturated fatty acids, or PUFAs, taken up from food or the host organism increased. A higher PUFA content may make cells more susceptible to damage caused by oxidative stress and may contribute to the increased death of ACC-deficient tumour cells.

“Our results show that the composition of membrane lipids and triglycerides shifts markedly in ACC-deficient tumours […] we considered it important to identify molecular switches within cells that could provide a link between fatty-acid availability and tumour-cell viability, and thereby tumour growth,” the authors write.

Disruption of fatty-acid synthesis switches off TORC1 growth signalling

One of the study’s most important findings is that the disruption of fatty-acid synthesis caused by ACC loss reduces the activity of the TORC1 complex, which controls cell growth. TORC1 regulates cell growth and division in response to nutrient, energy and hormonal signals; its inhibition can therefore lead to growth arrest and activation of processes associated with autophagy and cell death.

The researchers also showed that TORC1 inhibition caused by ACC deficiency is independent of insulin–PI3K signalling: genetically enhancing the insulin pathway was unable to restore the activity of the complex. The findings therefore indicate that fatty acids are not merely structural building blocks, but also contribute to maintaining TORC1 activity and consequently tumour growth independently of insulin signalling.

Ex vivo lipid supplementation confirms the direct role of fatty acids

Dorottya Károlyi, the study’s first author and a PhD student, developed an ex vivo lipid-supplementation method in which tumours removed from larvae were maintained under controlled conditions. Treating ACC-deficient tumours with oleic acid partially restored both tumour growth and TORC1 activity, while having no meaningful effect on control tumours. The result directly confirmed that tumour growth depends on the quantity and composition of the fatty acids available.

A possible new avenue for treating resistant tumours

In many types of human tumour, abnormally elevated activity of the insulin–PI3K–TORC1 signalling pathway supports rapid growth and may also contribute to the development of therapeutic resistance. The anti-tumour effects of compounds that inhibit fatty-acid synthesis have previously been investigated in several human cancer cell lines. The new findings suggest that inhibiting ACC may not only restrict cells’ own production of fatty acids, but may also reduce TORC1 activity and the capacity for tumour growth independently of insulin signalling.

This raises the possibility that ACC inhibitors could in future provide an adjunctive therapeutic option for tumours with elevated insulin–TORC1 signalling, particularly when the tumour has become less responsive to treatments targeting insulin or PI3K signalling.

It is important to emphasise, however, that the current findings are based on fruit-fly tumour models. Further studies in cell cultures and animal models, followed by clinical trials, will be required to determine their applicability to the treatment of human tumours.