PT - JOURNAL ARTICLE AU - Elena Panzilius AU - Felix Holstein AU - Marie Bannier-Hélaouët AU - Christine von Toerne AU - Ann-Christine Koenig AU - Stefanie M. Hauck AU - Hilary M. Ganz AU - José P. Friedmann Angeli AU - Marcus Conrad AU - Christina H. Scheel TI - A cell-density dependent metabolic switch sensitizes breast cancer cells to ferroptosis AID - 10.1101/417949 DP - 2018 Jan 01 TA - bioRxiv PG - 417949 4099 - http://biorxiv.org/content/early/2018/09/14/417949.short 4100 - http://biorxiv.org/content/early/2018/09/14/417949.full AB - Ferroptosis is a regulated form of necrotic cell death caused by the accumulation of lipid peroxides. It can be induced by inhibiting glutathione peroxidase 4 (GPX4), the key enzyme for lipid peroxides reduction from phospholipid membranes. Recent studies have identified metabolic and genetic contributors to ferroptosis. However, many mechanisms of resistance or sensitivity to ferroptosis remain unknown. Here, we show that low cell density sensitizes primary mammary epithelial and breast cancer cells to induction of ferroptosis by GPX4 inhibition, whereas high cell density confers resistance. This effect occurs irrespective of oncogenic signaling or cellular phenotype and is not directly correlated to an increase in lipid peroxides. Mechanistically, we show that low cell density induces liberation of fatty acids from lipid droplets by adipose triglyceride lipase (ATGL) to fuel β-oxidation. Thereby, lipid-mediated toxicity is increased and exceeds a death-inducing threshold once GPX4 function is impaired. In conclusion, low cell-density regulated ferroptosis might serve as a mechanism to protect epithelial tissue integrity with the potential to be exploited in order to target disseminated breast cancer cells.