Polyploid cancer cells surviving cisplatin reallocate central carbon sources to fuel antioxidant metabolism for survival.

Melvin Li, Bradley Priem, Luke V Loftus, Michael J Betenbaugh, Kenneth J Pienta, Sarah R Amend

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In one paragraph

Article in Molecular metabolism, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0citing papers in PubMed

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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

Update of
Drug-tolerant persister cells reallocate carbon sources to fuel antioxidant metabolism for survival.2026

5 · Who and what money

Authors and funding

6 authors.

Melvin LiCancer Ecology Center, The James Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA; Pharmacology and Molecular Sciences Program, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. Electronic address: mli154@jh.edu.

Bradley PriemDepartment of Chemical and Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA. Electronic address: bradleypriem@gmail.com.

Luke V LoftusCancer Ecology Center, The James Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. Electronic address: lloftus@cemm.at.

Michael J BetenbaughDepartment of Chemical and Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA. Electronic address: mjbeten@gmail.com.

Kenneth J PientaCancer Ecology Center, The James Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA; Pharmacology and Molecular Sciences Program, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. Electronic address: kpienta1@jhmi.edu.

Sarah R AmendCancer Ecology Center, The James Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA; Pharmacology and Molecular Sciences Program, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. Electronic address: samend2@jhmi.edu.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Therapy resistance is the leading cause of cancer-related deaths. Polyploid cancer cells mediate resistance through adaptive cell states transitions that promote survival and tumor recurrence. Here, we investigate metabolic differences between cisplatin-surviving polyploid cells and parental cancer cells using integrated fluxomics. Transcriptomic and proteomic profiling and extracellular flux analyses revealed that surviving cells upregulate glycolysis and gluconeogenesis while reducing oxidative phosphorylation, indicating a shift in central carbon metabolism. Isotope tracing and metabolic modeling demonstrate that surviving cells utilize glucose to fuel the pentose phosphate pathway (PPP) for NADPH generation and metabolize glutamine to provide carbons for the PPP via gluconeogenesis. Integrating our multi-omic datasets into a genome-scale model identified that surviving cells sustain antioxidant metabolism by decreasing fluxes of other NADPH-consuming reactions upon in silico PPP knockout. In addition, pathway-centric transcriptomic analysis revealed that high PPP and antioxidant gene expression correlated with poor survival outcomes in patients across multiple cancer types, demonstrating the clinical prognostic value of PPP and antioxidant metabolism. These findings reveal a systems-level shift in metabolism that maintains antioxidant activity for cell survival, highlighting potential targets and treatment paradigms to overcome therapy resistance.

Indexed as

AntioxidantsCarbonCisplatinNeoplasmsAntineoplastic AgentsCell Line, TumorCell SurvivalDrug Resistance, NeoplasmGluconeogenesisGlucoseGlycolysisHumansMetabolic ReprogrammingPentose Phosphate PathwayPolyploidyAntineoplastic AgentsAntioxidantsCarbonCisplatinGlucose(13)C-metabolic flux analysisCancer metabolismChemotherapy resistanceGenome scale metabolic modelingIntegrated fluxomics

Identifiers

PMID42009164

DOI10.1016/j.molmet.2026.102370

PMCPMC13158425

What Socratic holds

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LicenceCC BY

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.