Metastasis Slowed by Targeting Lipid Metabolism in Healthy Lung Cells

Metastatic cancer cells don't just consume resources in their new organs — they recruit and reprogram the healthy cells already there to serve them. A study from VIB-KU Leuven and the Francis Crick Institute, published in Cancer Discovery, shows exactly how that works in the lung, and suggests a way to interrupt it.

According to GEN, the researchers found that breast cancer metastases recruit alveolar type II cells — AT2 cells, the normal lung cells responsible for producing surfactant — and reprogram them into lipid feeder cells. The metastases secrete proteins that activate a transcription factor called SREBP-1 in AT2 cells, which ramps up expression of key lipid synthesis genes including FASN and GPAM. Those enzymes produce palmitate and other lipid species that the cancer cells consume.

The insight that matters beyond the basic biology: these lipids aren't just an energy source. According to GEN, complementary work from Sarah-Maria Fendt's lab at VIB-KU, published in Nature Cell Biology, found that cancer cells also use these lipids as signaling molecules — modifying proteins and reshaping their molecular identity to enable growth. "The key insight was that these lipids are not just used as an energy source," Fendt said, per GEN. "Instead, they initiate the molecular pathway that enables cancer cells to modify themselves and grow. When we interrupt this process, we can block metastatic growth."

When the researchers selectively deleted Fasn in AT2 cells in mice, lung metastasis growth was significantly impaired, according to GEN. The findings were reproduced across institutions — an important validation. "We were able to obtain the same results in different laboratories, with different models and with different techniques," said co-senior author Mariia Yuneva of the Francis Crick Institute, per GEN.

The clinical angle is patient selection. A few trials are already testing lipid-synthesis inhibitors, but identifying which patients respond has been difficult. According to GEN, the new data suggest patients whose metastases heavily recruit AT2 cells may be the most responsive — which gives researchers a biomarker hypothesis to test.

Analysis: The AT2 cell recruitment mechanism is a specific vulnerability that didn't exist before this study. Targeting FASN or GPAM systemically would affect many cell types, but the study shows that deleting Fasn selectively in AT2 cells is sufficient to impair metastasis in mice. Whether that selectivity can be achieved pharmacologically in humans — and whether the lipid signaling role is as critical in patients as it appears in models — is the open question.

Notebook: The lipid metabolism field in cancer has been inching toward this framing for years — the idea that lipids are signaling molecules, not just fuel, and that targeting synthesis enzymes affects more than just energy production. The Fendt lab's Nature Cell Biology work is the conceptual glue here. If the signaling role holds up, it changes which patients might benefit from FASN inhibitors and why.