Integrin Regulation of Ferroptosis in Breast Cancer
Technical Report,15 Jan 2018,14 Jan 2019
University of Massachusetts Worcester United States
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The hypothesis being tested in this proposal is that breast cancer cells, especially metastatic cells, are prone to rapid increases in ROS and lipid peroxidation caused by adverse micro-environmental conditions and that these oxidative bursts could have deleterious consequences including ferroptosis. Ferroptosis is defined as an iron-dependent, non-apoptotic form of programmed cell death characterized by the accumulation of intracellular soluble and lipid reactive oxygen species ROS. For this reason, breast tumor cells must acquire mechanisms to protect against oxidative bursts and ferroptosis to metastasize. Work accomplished during the second year of this proposal has demonstrated that matrix-detached breast carcinoma cells cluster spontaneously and that this clustering triggers an increase in lipid peroxidation that is sufficient to induce ferroptosis. We also found that clustering occurs by a mechanism that involves the cell adhesion protein PVRL4 also known as Nectin-4. We found that this clustering process allows these cells to survive by stimulating a PVRL4alpha6beta4Src signaling axis that sustains GPX4 expression and buffers against lipid peroxidation. These results indicate that ferroptosis induction depends on cell clustering in matrix-detached cells that lack alpha6beta4 and imply that the fate of matrix-detached cells can be determined by the state of their cellcell interactions.
- Medicine and Medical Research