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

Jianping He; Abigail M Abikoye; Brett P McLaughlin; Ryan S Middleton; Ryan Sheldon; Russell G Jones; Zachary T Schafer

doi:10.1016/j.isci.2023.106827

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

iScience. 2023 May 9;26(6):106827. doi: 10.1016/j.isci.2023.106827. eCollection 2023 Jun 16.

Authors

Jianping He^{1

2}, Abigail M Abikoye^{1

2}, Brett P McLaughlin^{1

2}, Ryan S Middleton^{1

2}, Ryan Sheldon³, Russell G Jones⁴, Zachary T Schafer^{1

2}

Affiliations

¹ Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.
² Boler-Parseghian Center for Rare & Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA.
³ Metabolomics and Bioenergetics Core, Van Andel Institute, Grand Rapids, MI 49503, USA.
⁴ Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA.

Abstract

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.

Keywords: Cancer; Cell biology.

Grants and funding

R01 CA262439/CA/NCI NIH HHS/United States