Evidence map›Paper›PMID 36411320›Full record

ArticleNature cancer2022

Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.

Christopher J Halbrook, Galloway Thurston, Seth Boyer, Cecily Anaraki, Jennifer A Jiménez, Amy McCarthy, Nina G Steele, Samuel A Kerk, Hanna S Hong, Lin Lin and 24 more

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

Article in Nature cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.

0numbers the graph read from it
0cells of the map it votes in
50citing papers in PubMed
6.8field-weighted citation impact, top 2% 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

50 citing papers in PubMed, 70 citations in OpenAlex.

  1. Article
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  8. Reductive stress in cancer immunology and targeted therapy.Acta biochimica et biophysica Sinica · 2026
    Review
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  10. ERO1A-positive tumor epithelial cells in colorectal cancer progression: a multi-omics perspective.Apoptosis : an international journal on programmed cell death · 2025
    Article
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

34 authors at 11 institutions in 2 countries.

Christopher J HalbrookDepartment of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA. chris.halbrook@uci.edu.ORCID http://orcid.org/0000-0002-3376-3114
Galloway ThurstonDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Seth BoyerDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Cecily AnarakiDepartment of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
Jennifer A JiménezDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Amy McCarthyCancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
Nina G SteeleDepartment of Surgery, University of Michigan, Ann Arbor, MI, USA.
Samuel A KerkDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0001-9786-2245
Hanna S HongDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0003-1202-2808
Lin LinDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Fiona V LawDepartment of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
Catherine FeltonCancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
Lorenzo ScipioniDepartment of Biomedical Engineering, University of California Irvine, Irvine, CA, USA.
Peter SajjakulnukitDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-8556-7481
Anthony AndrenDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Alica K BeutelDepartment of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
Rima SinghDepartment of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
Barbara S NelsonDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Fran Van Den BerghDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0003-4025-6863
Abigail S KrallDepartment of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.
Peter J MullenDepartment of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.
Li ZhangDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Sandeep BatraRiley Hospital for Children at Indiana University Health, Indianapolis, IN, USA.
Jennifer P MortonCancer Research UK Beatson Institute and Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
Ben Z StangerGastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Heather R ChristofkDepartment of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.ORCID http://orcid.org/0000-0002-8662-4425
Michelle A DigmanDepartment of Biomedical Engineering, University of California Irvine, Irvine, CA, USA.ORCID http://orcid.org/0000-0003-4611-7100
Daniel A BeardDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Andrea VialeDepartment of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Ji ZhangHerman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.ORCID http://orcid.org/0000-0002-9274-1767
Howard C CrawfordDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Marina Pasca di MaglianoDepartment of Surgery, University of Michigan, Ann Arbor, MI, USA.
Claus JorgensenCancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
Costas A LyssiotisDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. clyssiot@med.umich.edu.ORCID http://orcid.org/0000-0001-9309-6141
University of Michigan · USUniversity of California, Irvine · USUniversity of California, Los Angeles · USUniversity of Manchester · GBHenry Ford Health System · USCancer Research UK Scotland Institute · GBChapman University · USIndiana University Health · USIndiana University School of MedicineThe University of Texas MD Anderson Cancer Center · USUniversity of Pennsylvania · US

Funding

Univ.of Calif., Irvine Cancer Center Support GrantP30CA062203 · NCI · UNIVERSITY OF CALIFORNIA-IRVINE · PI Melanie Funes · 1994 to 2026
$57.9M
Intratumoral Metabolic Crosstalk Promotes Therapeutic Resistance in Pancreatic CancerR37CA237421 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Costas Andreas Lyssiotis · 2020 to 2026
$2.6M
Metabolic adaptation in lymphoid malignanciesR01CA244625 · NCI · INDIANA UNIVERSITY INDIANAPOLIS · PI ZHANG, JI · 2020 to 2024
$2.2M
Stromal metabolism promotes therapeutic resistance in pancreatic cancerR01CA248160 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LYSSIOTIS, COSTAS ANDREAS · 2020 to 2024
$2.0M
Targeting metabolic stress to induce pancreatic tumor cell deathR01CA244931 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LYSSIOTIS, COSTAS ANDREAS · 2020 to 2024
$1.9M
Disrupting macrophage metabolism to reduce immunosuppression and enhance therapy in pancreatic cancerR00CA241357 · NCI · UNIVERSITY OF CALIFORNIA-IRVINE · PI HALBROOK, CHRISTOPHER J. · 2020 to 2022
$778k
Cancer Research UK 19258Cancer Research UK 29996Cancer Research UK A19258Cancer Research UK A25236NCI NIH HHS P30 CA062203NCI NIH HHS R00 CA241357NCI NIH HHS R01 CA244625NCI NIH HHS R01 CA244931NCI NIH HHS R01 CA248160NCI NIH HHS R37 CA237421
6 · The paper itself

Abstract

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.

Indexed as

AdenocarcinomaPancreatic NeoplasmsAnimalsAsparagineHumansMiceSymbiosisTumor MicroenvironmentAsparagine

Identifiers

PMID36411320
PMCPMC9701142
OpenAlexW4309666883

What OpenQuestion holds

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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.