Theses Doctoral

Altered lipid metabolism in persister cells drives ferroptosis sensitivity

Reznik, Eduard

Mounting evidence implicates persister cancer cells as the key element of minimal residual disease (MRD) from which cancer relapse occurs. The observation that persister cells are differentially and specifically sensitive to ferroptosis, a unique form of metabolically-linked cell death, presents a critical weak point through which identification and targeting of persister cells in MRD may become possible. To identify biomarkers for targetable cells, the drivers of ferroptosis sensitivity in persister cells must be identified.

Using three chemotherapeutics and cell lines, we derived persister models across diverse tissues of origin and found that: 1) activating transcription factor 4 (ATF4), previously demonstrated as central to lung cancer persister state formation, is differentially expressed in prostate and fibrosarcoma persisters vs parentals, 2) proteins key to ferroptosis are underexpressed in persisters, and revert expression upon persister to parental reversion, 3) the lung persister lipidome is significantly rewired to drive ferroptosis and 4) upon persister to parental reversion and re-acquisition of ferroptosis resistance, the lipid signature also reverts back to a parental-like state, and 5) although ATF4 elimination in persisters does not revert ferroptosis sensitivity, mitochondrial elimination in persisters does abrogate ferroptotic sensitivity.

Collectively, these findings reveal the mechanism of persister ferroptosis sensitivity across multiple cancer types, opening up the possibility of leveraging ferroptosis for elimination of minimal residual disease.


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More About This Work

Academic Units
Cellular, Molecular and Biomedical Studies
Thesis Advisors
Stockwell, Brent R.
Ph.D., Columbia University
Published Here
February 21, 2024