Ryan P. Mansell, Sebastian Müller, Jia-Shu Yang, Sarah Innes-Gold, Sunny Das, Ferenc Reinhardt, Kim Sigmund, Vaishnavi V. Phadnis, Zhengpeng Wan, Jillian Stark, Daehee Hwang, Fabien Sindikubwabo, Laurène Syx, Nicolas Servant, Elinor Ng Eaton, Júlio L. Sampaio, George W. Bell, Prathapan Thiru, Amartya Viravalli, Amy Deik, Clary B. Clish, Paula T. Hammond, Roger D. Kamm, Adam E. Cohen, Ilya Levental, Natalie Boehnke, Victor W. Hsu, Kandice R. Levental, Raphaël Rodriguez, Robert A. Weinberg, Whitney S. Henry
Cancer cell fate has been widely ascribed to mutational changes within protein-coding genes associated with tumor suppressors and oncogenes. In contrast, the mechanisms through which the biophysical properties of membrane lipids influence cancer cell survival, dedifferentiation and metastasis have received little scrutiny. Here, we report that cancer cells endowed with high metastatic ability and cancer stem cell-like traits employ ether lipids to maintain low membrane tension and high membrane fluidity. Using genetic approaches and lipid reconstitution assays, we show that these ether lipid-regulated biophysical properties permit non-clathrin-mediated iron endocytosis via CD44, resulting in significant increases in intracellular redox-active iron and enhanced ferroptosis susceptibility. Using a combination of in vitro three-dimensional microvascular network systems and in vivo animal models, we show that loss of ether lipids from plasma membranes also strongly attenuates extravasation, metastatic burden and cancer stemness. These findings illuminate a mechanism whereby ether lipids in carcinoma cells serve as key regulators of malignant progression while conferring a unique vulnerability that can be exploited for therapeutic intervention. The contribution of ether lipid species in cancer cell fate has not been fully understood yet. Here the authors show that malignant cancer cells employ ether lipids to modulate membrane biophysical properties, enhancing iron endocytosis and ferroptosis susceptibility.