Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.

Journal

Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119

Informations de publication

Date de publication:
09 Oct 2023
Historique:
received: 07 07 2022
accepted: 06 09 2023
medline: 10 10 2023
pubmed: 10 10 2023
entrez: 9 10 2023
Statut: aheadofprint

Résumé

In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Here, we elucidate how 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism, blocks PDAC tumor growth and metastasis. We find that DON significantly reduces asparagine production by inhibiting asparagine synthetase (ASNS), and that the effects of DON are rescued by asparagine. As a metabolic adaptation, PDAC cells upregulate ASNS expression in response to DON, and we show that ASNS levels are inversely correlated with DON efficacy. We also show that L-asparaginase (ASNase) synergizes with DON to affect the viability of PDAC cells, and that DON and ASNase combination therapy has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of cotargeting adaptive responses to control PDAC progression.

Identifiants

DOI: 10.1038/s43018-023-00649-1 PMID: 37814011
pubmed: 37814011
doi: 10.1038/s43018-023-00649-1
pii: 10.1038/s43018-023-00649-1
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : NCI NIH HHS
ID : R01 CA207189
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA254806
Pays : United States

Informations de copyright

© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

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Auteurs

Maria Victoria Recouvreux (MV)

Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Shea F Grenier (SF)

Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Yijuan Zhang (Y)

Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Edgar Esparza (E)

Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Division of Surgical Sciences, Department of Surgery, University of California San Diego, La Jolla, CA, USA.

Guillem Lambies (G)

Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Cheska Marie Galapate (CM)

Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Swetha Maganti (S)

Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Karen Duong-Polk (K)

Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Deepika Bhullar (D)

Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Razia Naeem (R)

Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

David A Scott (DA)

Cancer Metabolism Core Resource, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
ORCID: 0000-0002-8668-2449

Andrew M Lowy (AM)

Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, USA.

Hervé Tiriac (H)

Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Division of Surgical Sciences, Department of Surgery, University of California San Diego, La Jolla, CA, USA.
ORCID: 0000-0001-5039-6750

Cosimo Commisso (C)

Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. ccommisso@sbpdiscovery.org.
ORCID: 0000-0002-7884-9210

Classifications MeSH