Lung metastasis remains one of the turning points in cancer progression, in part because the lung provides a uniquely supportive niche for incoming tumor cells. Among the resident cells that shape this microenvironment, alveolar type II (AT2) cells—normally responsible for producing surfactant and maintaining lung structure—also generate lipids that metastatic cancer cells can exploit. Now, researchers from the VIB‑KU Leuven Center for Cancer Biology and the Francis Crick Institute have uncovered how metastatic breast cancer cells co‑opt these healthy lung cells to fuel their growth, and how disrupting this lipid supply can slow metastasis.
In a study published in Cancer Discovery in a paper titled, “Targeting the Lipid Metabolism Proteins FASN and GPAM in Alveolar Type II Cells Decreases Lung Metastasis,” the teams showed that established lung metastases actively recruit AT2 cells and reprogram them into lipid feeder cells. “We discovered that cancer cells recruit AT2 cells and reprogram them to produce more lipids for them,” said first author Xiao‑Zheng Liu, PhD, a postdoc at VIB‑KU Leuven, in a press release. Using spatial analysis in mouse models and patient samples, the researchers found that AT2 cells proliferate in the immediate vicinity of metastases and upregulate key lipid synthesis genes.
“Mechanistically, the metastasis secretome activates the transcription factor sterol regulatory element–binding transcription factor 1 (SREBP-1) in AT2 cells, enhancing the expression of key de novo lipid synthesis genes, including fatty acid synthase (FASN) and glycerol-3-phosphate acyltransferase 1 (GPAM),” the authors wrote. These enzymes boost de novo lipid production, supplying cancer cells with palmitate and other lipid species. While lipids have long been viewed primarily as energy sources, complementary work from the Fendt lab, published in Nature Cell Biology, shows that cancer cells also use these lipids as signaling molecules to modify proteins and reshape their molecular identity. “The key insight was that these lipids are not just used as an energy source,” said senior author Sarah‑Maria Fendt, PhD, of VIB-KU. “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.”
To test whether AT2‑derived lipids are required for metastasis, the researchers selectively deleted Fasn in AT2 cells. “Deleting Fasn selectively in AT2 cells or targeting FASN and GPAM systemically significantly impairs lung metastasis growth in mice,” the authors wrote. Importantly, the findings were reproducible across institutions. “We were able to obtain the same results in different laboratories, with different models and with different techniques,” noted co‑senior author Mariia Yuneva, PhD, of the Francis Crick Institute. “Bringing our complementary expertise together made the study very robust.”
A few clinical trials are already evaluating lipid‑synthesis inhibitors, but understanding which patients will benefit most remains difficult. The new findings suggest that patients whose metastases heavily recruit AT2 cells may be the most responsive. “This insight helps refine the group of patients who may benefit most from these therapies,” said Fendt.
Beyond breast cancer metastasis, the results hint at a broader role for AT2‑cell lipid metabolism in lung‑resident tumors.
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