PXD046786

PXD046786 is an original dataset announced via ProteomeXchange.

Title	Inhibition of choline metabolism in an angioimmunoblastic T cell lymphoma preclinical model reveals a new treatment option
Description	Background: Angioimmunoblastic T-cell lymphoma (AITL) is a malignancy with very poor survival outcome, in need of new more specific therapeutic regimen. The drivers of malignancy in this disease are CD4+ follicular helper T cells (Tfh). The metabolism of these malignant Tfh cells was not yet elucidated. Therefore, we decided to identify their metabolic requirements with the objective to propose a novel therapeutic option. Methods: To reveal the prominent metabolic pathways used by the AITL lymphoma cells, leveraged on our previously established AITL mouse model by crossing metabolomic and proteomic data of murine AITL cells. We confirmed these results using AITL patient and healthy T cell expression data. Results: Strikingly, the mAITL Tfh cells were highly dependent on the second branch of the Kennedy pathway, the choline lipid pathway, responsible for the production of the major membrane constituent phosphatidylcholine. Moreover, gene expression data from Tfh cells isolated from AITL patient tumors, confirmed the upregulation of the choline lipid pathway. Several enzymes involved in this pathway such as choline kinase, catalyzing the first step in the phosphatidylcholine pathway, respectively, are upregulated in multiple tumors other than AITL. Here we showed that treatment of our mAITL preclinical mouse model with the fatty acid oxydation inhibitor, etomoxir, significantly increased their survival and even reverted the exhausted CD8 T cells in the tumor into potent cytotoxic anti-tumor cells. Specific inhibition of Chok confirmed the importance of the phosphatidylcholine production pathway in the neoplastic CD4+ T cells, since it irradicated almost all the mAITL Tfh cells from the tumors. Finally, the same inhibitor induced in human AITL lymphoma biopsies cell death of the majority of the hAITL PD-1high neoplastic cells. Conclusion: Our results suggest that interfering with the choline metabolism in AITL might represent a new therapeutic strategy for these patients.
HostingRepository	PRIDE
AnnounceDate	2024-04-04
AnnouncementXML	Submission_2024-04-04_05:01:57.213.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Matteo Pecoraro
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-08 07:55:44	ID requested
⏵ 1	2024-04-04 05:01:58	announced

10.1186/s13046-024-02952-w;

Krug A, Tosolini M, Madji Hounoum B, Fourni, é JJ, Geiger R, Pecoraro M, Emond P, Gaulard P, Lemonnier F, Ricci JE, Verhoeyen E, Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment. J Exp Clin Cancer Res, 43(1):43(2024) [pubmed]

submitter keyword: choline kinase,choline, AITL, lipid metabolism, CDP-ethanolamine pathway, T cell lymphoma, CDP-choline pathway, cancer therapy

Els Verhoeyen
contact affiliation	Université Côte d’Azur, INSERM, C3M, 06204 Nice, France. CIRI, Université de Lyon; INSERM U1111; ENS de Lyon; University Lyon1; CNRS, UMR5308, 69007 Lyon, France
contact email	els.verhoyen@ens-lyon.fr
lab head
Matteo Pecoraro
contact affiliation	Institute for Research in Biomedicine, Via Vincenzo Vela 6 - CH-6500 Bellinzona
contact email	matteo.pecoraro@irb.usi.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD046786
     1. Label: PRIDE project
     2. Name: Inhibition of choline metabolism in an angioimmunoblastic T cell lymphoma preclinical model reveals a new treatment option