Evidence map›Paper›PMID 28678785›Full record

ArticleNature2017

Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.

Vasanthi S Viswanathan, Matthew J Ryan, Harshil D Dhruv, Shubhroz Gill, Ossia M Eichhoff, Brinton Seashore-Ludlow, Samuel D Kaffenberger, John K Eaton, Kenichi Shimada, Andrew J Aguirre and 30 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1,161 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
1,161citing papers in PubMed, 1 pooled it
76.3field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1,161 citing papers in PubMed, 1 synthesis or guideline pooled it, 1,941 citations in OpenAlex.

  1. Interaction of HIF-1a with various cell death pathways in tumor immune microenvironment (TIME).Apoptosis : an international journal on programmed cell death · 2026
    Pooled it
  2. AA-Induced Lipid Peroxidation at the Center of Tumor Cell Apoptosis and Ferroptosis.Reviews of physiology, biochemistry and pharmacology · 2027
    Review
  3. Physiological Significance and Functions of AA.Reviews of physiology, biochemistry and pharmacology · 2027
    Review
  4. Review
  5. Review
  6. Review
  7. Review
  8. Circular RNAs in ferroptosis regulation and tumor progression of gynecological and breast cancers: molecular mechanisms and therapeutic potential.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026
    Review
  9. Targeted extracellular degradation of LRP8 promotes ferroptosis in cancer cells.Proceedings of the National Academy of Sciences of the United States of America · 2026
    Article
  10. Article
  11. Article
  12. Article
  13. Article
  14. The Emerging Role of Ferroptosis in Pediatric Cancer Biology and Therapy.International journal of molecular sciences · 2026
    Review
  15. Article
  16. Article
  17. Review
  18. Article
  19. Review
  20. Article

1,101 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

40 authors at 12 institutions in 2 countries.

Vasanthi S ViswanathanBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Matthew J RyanBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Harshil D DhruvCancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th Street, Phoenix, Arizona 85004, USA.
Shubhroz GillBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Ossia M EichhoffDepartment of Dermatology, University of Zurich, University Hospital of Zurich, Wagistrasse 14, CH-8952, Schlieren, Zürich, Switzerland.
Brinton Seashore-LudlowBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Samuel D KaffenbergerHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
John K EatonBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Kenichi ShimadaLaboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
Andrew J AguirreBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Srinivas R ViswanathanBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Shrikanta ChattopadhyayBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Pablo TamayoBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Wan Seok YangDepartment of Biological Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York 11439, USA.
Matthew G ReesBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Sixun ChenBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Zarko V BoskovicBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Sarah JavaidMassachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, Massachusetts 02129, USA.
Cherrie HuangBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Xiaoyun WuBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Yuen-Yi TsengBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Elisabeth M RoiderDepartment of Dermatology, University of Zurich, University Hospital of Zurich, Wagistrasse 14, CH-8952, Schlieren, Zürich, Switzerland.
Dong GaoHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
James M ClearyDepartment of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Brian M WolpinDepartment of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Jill P MesirovBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Daniel A HaberMassachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, Massachusetts 02129, USA.
Jeffrey A EngelmanOncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA.
Jesse S BoehmBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Joanne D KotzBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Cindy S HonBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Yu ChenHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
William C HahnBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Mitchell P LevesqueDepartment of Dermatology, University of Zurich, University Hospital of Zurich, Wagistrasse 14, CH-8952, Schlieren, Zürich, Switzerland.
John G DoenchBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Michael E BerensCancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th Street, Phoenix, Arizona 85004, USA.
Alykhan F ShamjiBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Paul A ClemonsBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Brent R StockwellDepartment of Biological Sciences, Department of Chemistry, Columbia University, 550 West 120th Street, New York, New York 10027, USA.
Stuart L SchreiberBroad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Broad Institute · USMemorial Sloan Kettering Cancer Center · USDana-Farber Cancer Institute · USTranslational Genomics Research Institute · USUniversity Hospital of Zurich · CHCenter for Systems Biology · USColumbia University · USHoward Hughes Medical Institute · USMassachusetts General Hospital · USNovartis (United States) · USSt. John's University · USUniversity of Zurich · CH

Funding

X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Nicholas D Socci · 1985 to 2026
$347.4M
Harvard Clinical and Translational Science CenterUL1TR001102 · NCATS · HARVARD MEDICAL SCHOOL · PI NADLER, LEE MARSHALL · 2013 to 2017
$106.2M
SPORE In Prostate CancerP50CA092629 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Yu Chen, MICHAEL J MORRIS · 2001 to 2026
$63.0M
Pilot & Feasibility ProgramP30DK043351 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI RAYMOND T CHUNG · 1991 to 2026
$35.3M
SYNTHESIS OF MATERIALS WITH PHYSIOLOGICAL PROPERTIESR01GM038627 · NIGMS · YALE UNIVERSITY · PI SCHREIBER, STUART L · 1987 to 2017
$10.5M
The Dana-Farber Cancer Institute Cancer Target Discovery and Development CenterU01CA176058 · NCI · DANA-FARBER CANCER INST · PI HAHN, WILLIAM C. · 2013 to 2021
$7.8M
Modeling Metastasis and Acquired Drug Resistance Using Circulating Tumor CellsR01CA129933 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Daniel A. Haber · 2008 to 2026
$7.5M
Supporting Integrative Genomic Analysis Users with GenePatternR01GM074024 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MESIROV, JILL P. · 2005 to 2019
$6.6M
Defining the functions and translational potential of ferroptosisR35CA209896 · NCI · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI STOCKWELL, BRENT R. · 2016 to 2022
$6.5M
Targeting vulnerabilities of therapy-resistant cancer cell states with small moleculesU01CA217848 · NCI · BROAD INSTITUTE, INC. · PI SCHREIBER, STUART L · 2017 to 2021
$5.8M
Knowledge-based Gene Expression Analysis for Biomedical and Cancer ResearchR01CA121941 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MESIROV, JILL P. · 2006 to 2016
$5.1M
Chemical Genetic Profiling of Engineered Tumor CellsR01CA097061 · NCI · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · PI STOCKWELL, BRENT R. · 2002 to 2016
$4.8M
Howard Hughes Medical InstituteNCATS NIH HHS UL1 TR001102NCI NIH HHS K08 CA218420NCI NIH HHS P30 CA008748NCI NIH HHS P50 CA092629NCI NIH HHS R01 CA097061NCI NIH HHS R01 CA121941NCI NIH HHS R01 CA129933NCI NIH HHS R01 CA154480NCI NIH HHS R01 CA161061NCI NIH HHS R01 CA193837NCI NIH HHS R01 CA208100NCI NIH HHS R35 CA209896NCI NIH HHS U01 CA168397NCI NIH HHS U01 CA176058NCI NIH HHS U01 CA176152NCI NIH HHS U01 CA199253NCI NIH HHS U01 CA217848NCI NIH HHS U24 CA194107NIDDK NIH HHS P30 DK043351NIGMS NIH HHS R01 GM038627NIGMS NIH HHS R01 GM074024NIGMS NIH HHS R01 GM085081
6 · The paper itself

Abstract

Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.

Indexed as

CadherinsCell DeathCell LineageCell Line, TumorCell TransdifferentiationDrug Resistance, NeoplasmEpithelial-Mesenchymal TransitionGlutathione PeroxidaseHumansIronLipid PeroxidationLipid PeroxidesMaleMelanomaMesodermNeoplasmsBRAF protein, humanCadherinsGlutathione PeroxidaseIronLipid PeroxidesPhospholipid Hydroperoxide Glutathione PeroxidaseProto-Oncogene Proteins B-rafZEB1 protein, humanZinc Finger E-box-Binding Homeobox 1

Identifiers

PMID28678785
PMCPMC5667900
OpenAlexW2727828415

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Registered trials

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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 OpenQuestion graph.