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. van Deventer; Rinke Stienstra; Julia Jellusova; Martin Giera; Luciana Hannibal; Ute Spiekerkoetter; Martin ter Beest; Celia R. Berkers; Annemiek B. van Spriel

doi:10.1038/s41467-022-33138-7

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. van Deventer, Rinke Stienstra, Julia Jellusova, Martin Giera, Luciana Hannibal, Ute Spiekerkoetter, Martin ter Beest, Celia R. Berkers, Annemiek B. van Spriel^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	5371
Pages (from-to)	1-18
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33138-7
Publication status	Published - 13 Sept 2022

Bibliographical note

Funding Information:
A.B.v.S. is supported by the Netherlands Organization for Scientific Research NWO Gravitation Programme 2013 grant (ICI 00023), ZonMW (project 09120012010023), the Dutch Cancer Society (KWF) (11618/2018 and 12949/2020), and was awarded a European Research Council Consolidator Grant (Secret Surface, 724281). C.R.B. is supported by grant ICI-00014 from the Institute for Chemical Immunology, funded by the NWO Gravitation Programme. R.S. was supported by an IMI grant (Hyporesolve) and a grant from Health Holland (Timid). N.B. and M.G. were partially supported by NWO project 184.034.019. The authors thank M. van den Brand for providing the patient DLBCL tissue samples, I. van Raaij for the Oil red O staining protocol and control samples. The authors are very grateful to Tsuyoshi Shinozuka for providing compound 5k and 12a.

Publisher Copyright:
© 2022, The Author(s).

Funding

A.B.v.S. is supported by the Netherlands Organization for Scientific Research NWO Gravitation Programme 2013 grant (ICI 00023), ZonMW (project 09120012010023), the Dutch Cancer Society (KWF) (11618/2018 and 12949/2020), and was awarded a European Research Council Consolidator Grant (Secret Surface, 724281). C.R.B. is supported by grant ICI-00014 from the Institute for Chemical Immunology, funded by the NWO Gravitation Programme. R.S. was supported by an IMI grant (Hyporesolve) and a grant from Health Holland (Timid). N.B. and M.G. were partially supported by NWO project 184.034.019. The authors thank M. van den Brand for providing the patient DLBCL tissue samples, I. van Raaij for the Oil red O staining protocol and control samples. The authors are very grateful to Tsuyoshi Shinozuka for providing compound 5k and 12a.

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Peeters, R., Cuenca-Escalona, J., Zaal, E. A., Hoekstra, A. T., Balvert, A. C. G., Vidal-Manrique, M., Blomberg, N., van Deventer, S. J., Stienstra, R., Jellusova, J., Giera, M., Hannibal, L., Spiekerkoetter, U., ter Beest, M., Berkers, C. R., & van Spriel, A. B. (2022). Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37. Nature Communications, 13(1), 1-18. Article 5371. https://doi.org/10.1038/s41467-022-33138-7

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title = "Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37",

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.",

author = "Rens Peeters and Jorge Cuenca-Escalona and Zaal, {Esther A.} and Hoekstra, {Anna T.} and Balvert, {Anouk C.G.} and Marcos Vidal-Manrique and Niek Blomberg and {van Deventer}, {Sjoerd J.} and Rinke Stienstra and Julia Jellusova and Martin Giera and Luciana Hannibal and Ute Spiekerkoetter and {ter Beest}, Martin and Berkers, {Celia R.} and {van Spriel}, {Annemiek B.}",

note = "Funding Information: A.B.v.S. is supported by the Netherlands Organization for Scientific Research NWO Gravitation Programme 2013 grant (ICI 00023), ZonMW (project 09120012010023), the Dutch Cancer Society (KWF) (11618/2018 and 12949/2020), and was awarded a European Research Council Consolidator Grant (Secret Surface, 724281). C.R.B. is supported by grant ICI-00014 from the Institute for Chemical Immunology, funded by the NWO Gravitation Programme. R.S. was supported by an IMI grant (Hyporesolve) and a grant from Health Holland (Timid). N.B. and M.G. were partially supported by NWO project 184.034.019. The authors thank M. van den Brand for providing the patient DLBCL tissue samples, I. van Raaij for the Oil red O staining protocol and control samples. The authors are very grateful to Tsuyoshi Shinozuka for providing compound 5k and 12a. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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month = sep,

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doi = "10.1038/s41467-022-33138-7",

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Peeters, R, Cuenca-Escalona, J, Zaal, EA, Hoekstra, AT, Balvert, ACG, Vidal-Manrique, M, Blomberg, N, van Deventer, SJ, Stienstra, R, Jellusova, J, Giera, M, Hannibal, L, Spiekerkoetter, U, ter Beest, M, Berkers, CR & van Spriel, AB 2022, 'Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37', Nature Communications, vol. 13, no. 1, 5371, pp. 1-18. https://doi.org/10.1038/s41467-022-33138-7

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T1 - Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37

AU - Peeters, Rens

AU - Cuenca-Escalona, Jorge

AU - Zaal, Esther A.

AU - Hoekstra, Anna T.

AU - Balvert, Anouk C.G.

AU - Vidal-Manrique, Marcos

AU - Blomberg, Niek

AU - van Deventer, Sjoerd J.

AU - Stienstra, Rinke

AU - Jellusova, Julia

AU - Giera, Martin

AU - Hannibal, Luciana

AU - Spiekerkoetter, Ute

AU - ter Beest, Martin

AU - Berkers, Celia R.

AU - van Spriel, Annemiek B.

N1 - Funding Information: A.B.v.S. is supported by the Netherlands Organization for Scientific Research NWO Gravitation Programme 2013 grant (ICI 00023), ZonMW (project 09120012010023), the Dutch Cancer Society (KWF) (11618/2018 and 12949/2020), and was awarded a European Research Council Consolidator Grant (Secret Surface, 724281). C.R.B. is supported by grant ICI-00014 from the Institute for Chemical Immunology, funded by the NWO Gravitation Programme. R.S. was supported by an IMI grant (Hyporesolve) and a grant from Health Holland (Timid). N.B. and M.G. were partially supported by NWO project 184.034.019. The authors thank M. van den Brand for providing the patient DLBCL tissue samples, I. van Raaij for the Oil red O staining protocol and control samples. The authors are very grateful to Tsuyoshi Shinozuka for providing compound 5k and 12a. Publisher Copyright: © 2022, The Author(s).

PY - 2022/9/13

Y1 - 2022/9/13

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Funding

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