Researchers co-led by Ludwig MIT Co-director emeritus Robert Weinberg, alumnus Whitney Henry—who now leads her own lab at MIT—and a colleague at the Institut Curie in France employed a combination of genetic approaches, lipid reconstitution assays, three-dimensional microvascular network systems and animal models to examine how ether lipids in the membrane contribute to cancer cell metastasis and survival. Highly drug-resistant stem-like cancer cells (CSCs) with mesenchymal traits—those essential to metastasis, such as motility and structural plasticity—tend to accumulate iron. The element is essential to cellular energy generation. But it also makes the cells susceptible to iron-dependent cell death, or ferroptosis, which is fueled by the oxidation of membrane lipids. The researchers previously found that ether lipids are major substrates for such oxidation. Robert, Whitney and colleagues reported in a January publication in Nature Communications that ether lipids support motility and morphological plasticity by establishing a low tension and high fluidity in the CSC’s external membranes. Further, they enable the clathrin-free, CD44-mediated uptake and hoarding of iron. Accordingly, loss of ether lipids from the membrane compromises the stemness of the cancer cells as well as their extravasation, a key step in metastasis. Ether lipid loss, the researchers showed, diminishes metastatic burden in mouse models. So a membrane property that confers a functional advantage to metastatic cells also exacts a cost: ferroptotic vulnerability.
Ether lipids influence cancer cell fate by modulating iron uptake
Nature Communications, 2026 January 27