Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37

Rens Peeters, Jorge Cuenca-Escalona, Esther A. Zaal, Anna T. Hoekstra, Anouk C. G. Balvert, Marcos Vidal-Manrique, Niek Blomberg, Sjoerd J. Deventer, Rinke Stienstra, Julia Jellusova, Martin Giera, Luciana Hannibal, Ute Spiekerkoetter, Martin Beest, Celia R. Berkers and Annemiek B. Spriel ()
Additional contact information
Rens Peeters: Radboud University Medical Centre
Jorge Cuenca-Escalona: Radboud University Medical Centre
Esther A. Zaal: Utrecht University
Anna T. Hoekstra: Utrecht University
Anouk C. G. Balvert: Radboud University Medical Centre
Marcos Vidal-Manrique: Radboud University Medical Centre
Niek Blomberg: Leiden University Medical Centre
Sjoerd J. Deventer: Radboud University Medical Centre
Rinke Stienstra: Wageningen University
Julia Jellusova: Technical University Munich
Martin Giera: Leiden University Medical Centre
Luciana Hannibal: Medical Centre - University of Freiburg
Ute Spiekerkoetter: Medical Centre - University of Freiburg
Martin Beest: Radboud University Medical Centre
Celia R. Berkers: Utrecht University
Annemiek B. Spriel: Radboud University Medical Centre

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract The importance of fatty acid (FA) metabolism in cancer is well-established, yet the mechanisms underlying metabolic reprogramming remain elusive. Here, we identify tetraspanin CD37, a prognostic marker for aggressive B-cell lymphoma, as essential membrane-localized inhibitor of FA metabolism. Deletion of CD37 on lymphoma cells results in increased FA oxidation shown by functional assays and metabolomics. Furthermore, CD37-negative lymphomas selectively deplete palmitate from serum in mouse studies. Mechanistically, CD37 inhibits the FA transporter FATP1 through molecular interaction. Consequently, deletion of CD37 induces uptake and processing of exogenous palmitate into energy and essential building blocks for proliferation, and inhibition of FATP1 reverses this phenotype. Large lipid deposits and intracellular lipid droplets are observed in CD37-negative lymphoma tissues of patients. Moreover, inhibition of carnitine palmitoyl transferase 1 A significantly compromises viability and proliferation of CD37-deficient lymphomas. Collectively, our results identify CD37 as a direct gatekeeper of the FA metabolic switch in aggressive B-cell lymphoma.

Date: 2022
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DOI: 10.1038/s41467-022-33138-7

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