Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells

Cancer cells often acquire resistance to cell death programs induced by loss of integrin-mediated attachment to extracellular matrix (ECM). Given that adaptation to ECM-detached conditions can facilitate tumor progression and metastasis, there is significant interest in effective elimination of ECM-detached cancer cells. Here, we find that ECM-detached cells are remarkably resistant to the induction of ferroptosis. Although alterations in membrane lipid content are observed during ECM detachment, it is instead fundamental changes in iron metabolism that underlie resistance of ECM-detached cells to ferroptosis. More specifically, our data demonstrate that levels of free iron are low during ECM detachment because of changes in both iron uptake and iron storage. In addition, we establish that lowering the levels of ferritin sensitizes ECM-detached cells to death by ferroptosis. Taken together, our data suggest that therapeutics designed to kill cancer cells by ferroptosis may be hindered by lack of efficacy toward ECM-detached cells.

Automated summary

Cancer cells that have detached from the extracellular matrix (ECM) are resistant to cell death induced by ferroptosis, a type of programmed cell death. The resistance is not caused by changes in membrane lipid content, but by alterations in iron metabolism, resulting in low levels of free iron. Lowering the levels of ferritin, a protein that stores iron, can sensitize ECM-detached cells to ferroptosis. This finding suggests that therapeutics targeting ferroptosis may be ineffective against cancer cells detached from the ECM.