Heterogeneous, Population-Level Drug-Tolerant Persisters Exhibit Ion-Channel Remodeling and Ferroptosis Susceptibility

Heterogeneous, population-level drug-tolerant persisters exhibit ion-channel remodeling and ferroptosis susceptibility | bioRxiv Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results Heterogeneous, population-level drug-tolerant persisters exhibit ion-channel remodeling and ferroptosis susceptibility Corey E. Hayford , Blake Baleami , Philip E. Stauffer , B. Bishal Paudel , Aziz Al’Khafaji , Amy Brock , Vito Quaranta , Darren R. Tyson , View ORCID Profile Leonard A. Harris doi: https://doi.org/10.1101/2022.02.03.479045 Corey E. Hayford 1 Chemical and Physical Biology Graduate Program, Vanderbilt University School of Medicine , Nashville, TN, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Blake Baleami 2 Human Genetics Graduate Program, Vanderbilt University School of Medicine , Nashville, TN, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Philip E. Stauffer 1 Chemical and Physical Biology Graduate Program, Vanderbilt University School of Medicine , Nashville, TN, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site B. Bishal Paudel 1 Chemical and Physical Biology Graduate Program, Vanderbilt University School of Medicine , Nashville, TN, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Aziz Al’Khafaji 3 Cell and Molecular Biology Graduate Program, Integrated Life Sciences, University of Texas at Austin , TX, USA 4 Department of Biomedical Engineering, University of Texas at Austin , TX, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Amy Brock 3 Cell and Molecular Biology Graduate Program, Integrated Life Sciences, University of Texas at Austin , TX, USA 4 Department of Biomedical Engineering, University of Texas at Austin , TX, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Vito Quaranta 5 Department of Biochemistry, Vanderbilt University School of Medicine , Nashville, TN, USA 6 Department of Pharmacology, Vanderbilt University School of Medicine , Nashville, TN, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Darren R. Tyson 6 Department of Pharmacology, Vanderbilt University School of Medicine , Nashville, TN, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: darren.tyson{at}duke.edu harrisl{at}uark.edu Leonard A. Harris 7 Department of Biomedical Engineering, University of Arkansas , Fayetteville, AR, USA 8 Interdisciplinary Graduate Program in Cell and Molecular Biology, University of Arkansas , Fayetteville, AR, USA 9 Cancer Biology Program, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences , Little Rock, AR, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Leonard A. Harris For correspondence: darren.tyson{at}duke.edu harrisl{at}uark.edu Abstract Full Text Info/History Metrics Supplementary material Preview PDF ABSTRACT Drug-tolerant persisters (DTPs) represent a major obstacle to durable responses in targeted cancer therapy. DTPs are commonly described as distinct single-cell states that survive drug treatment via reversible, non-genetic mechanisms and drive tumor recurrence. Recent work demonstrates that multiple DTPs can coexist, reflecting diversity in lineage, signaling programs, or stress responses. However, each DTP is still generally viewed as a uniform cellular phenotype. Building on our prior work describing a population-level DTP termed “idling” [Paudel et al., Biophys. J . (2018) 114, 1499–1511], here we present evidence supporting a fundamentally different view: that DTPs are not single-cell states, but rather heterogeneous populations composed of multiple sub-states with distinct division and death rates that balance to produce near-zero net population growth. Using single-cell transcriptomics and lineage barcoding, we identify multiple phenotypic states within idling DTP populations, with reduced heterogeneity compared to untreated populations, and find that idling DTP cells emerge from nearly all lineages. Transcriptomic and functional analyses further reveal altered ion-channel activity in idling DTPs, which we confirm experimentally. Moreover, drug-response assays reveal increased susceptibility of idling DTPs to ferroptosis, a non-apoptotic form of regulated cell death, indicating the emergence of vulnerabilities associated with drug tolerance. Altogether, our results support a population-level view of tumor drug tolerance in which DTPs comprise stable collections of phenotypic states, shaped by treatment-defined phenotypic landscapes, which are potentially vulnerable to subsequent interventions. This perspective implies that eradicating DTPs will require a fundamental shift away from cell-type-centric strategies toward sequential treatments that progressively reduce phenotypic heterogeneity by modulating the molecular and cellular processes that establish the DTP landscape, an approach previously termed “targeted landscaping.” Competing Interest Statement V.Q. is an academic cofounder and equity holder of Duet BioSystems and shareholder of Incendia Therapeutics. The other authors declare no competing interests. Footnotes Changed an affiliation and added funding information for A. Brock. Also made some small edits to the text and added an additional citation. Funder Information Declared National Institutes of Health, https://ror.org/01cwqze88 , F31-CA221147 , T32-GM065086 National Institutes of Health, https://ror.org/01cwqze88 , T32-CA119925 National Institutes of Health, https://ror.org/01cwqze88 , T32-MH064913 National Institutes of Health, https://ror.org/01cwqze88 , U54-CA113007 National Institutes of Health , R50-CA243783 National Institutes of Health , K22-CA237857 United States National Library of Medicine, https://ror.org/0060t0j89 , NLM 5T15-LM007450-14 Vanderbilt Institute for Clinical and Translational Research , VR16721 , VR16721.1 U.S. National Science Foundation , 1937963 National Institutes of Health , R01-CA255536 , U01-CA253540 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted May 08, 2026. 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Bishal Paudel , Aziz Al’Khafaji , Amy Brock , Vito Quaranta , Darren R. Tyson , Leonard A. Harris bioRxiv 2022.02.03.479045; doi: https://doi.org/10.1101/2022.02.03.479045 Share This Article: Copy Citation Tools Heterogeneous, population-level drug-tolerant persisters exhibit ion-channel remodeling and ferroptosis susceptibility Corey E. Hayford , Blake Baleami , Philip E. Stauffer , B. Bishal Paudel , Aziz Al’Khafaji , Amy Brock , Vito Quaranta , Darren R. Tyson , Leonard A. 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