Abstract
Ferroptotic cell death is mediated by cell contact and Hippo pathway members, including NF2 and YAP.
Major Finding: Ferroptotic cell death is mediated by cell contact and Hippo pathway members, including NF2 and YAP.
Concept: NF2 inactivation sensitizes cancer cells to ferroptosis in cells and mouse models.
Impact: Understanding susceptibility to ferroptotic cell death could guide development of ferroptosis-inducing therapies.
Ferroptosis is a form of iron-dependent programmed cell death implicated in cancer; notably, mesenchymal and metastatic cancer cells are very susceptible to ferroptosis. Wu, Minikes, and colleagues investigated the mechanisms behind this susceptibility, finding that ferroptosis was regulated by cadherin-mediated intercellular interactions. In multiple human epithelial cancer cell lines and 3-D epithelial tumor spheroids, increased cell density correlated with resistance to ferroptosis in almost all lines. Higher E-cadherin (ECAD) expression levels were associated with increased resistance to ferroptosis, and inhibition of ECAD dimerization made confluent cells more susceptible to ferroptosis. ECAD and Hippo signaling negatively regulated ferroptosis in a cell density–dependent manner, with knockdown of ECAD or Hippo pathway members resulting in increased ferroptosis in cancer cells and spheroids. Malignant mesothelioma often exhibits heterozygous deletion or loss-of-function mutations in the Hippo pathway gene NF2 or inactivation of additional pathway members LATS1 or LATS2, prompting an investigation of NF2 status and ferroptosis sensitivity in human malignant mesothelioma cell lines. All NF2–wild-type cells were relatively insensitive to ferroptosis under conditions in which NF2-mutant cells were able to undergo ferroptosis, and restoration of NF2 inhibited ferroptosis in NF2-mutant spheroids. Cells with a mutant version of YAP (which lies downstream of LATS1 and LATS2 in the Hippo pathway) that cannot be phosphorylated—and, thus, cannot be inactivated—were substantially more susceptible to ferroptosis at high density or in spheroids, and YAP knockout desensitized NF2-depleted cells to ferroptosis. Additionally, ECAD depletion, NF2 knockdown, or YAP overexpression led to upregulation of the ferroptosis modulators ACSL4 and TFRC, and increased cell density correlated with reduced expression of ACSL4 and TFRC. In a mouse model of malignant mesothelioma, genetic inactivation of NF2 made cancer cells more susceptible to ferroptosis. Together, these findings elucidate how NF2–YAP signaling mediates ferroptosis in cancer cells and suggest that developing therapies based on exploiting ferroptosis susceptibility, possibly applied to patients based on their genetic profiles, may be feasible.
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