Inhibition of fatty acid synthesis induces differentiation and reduces tumor burden in childhood neuroblastoma

María Victoria Ruiz-Pérez, Lourdes Sainero-Alcolado, Ganna Oliynyk, Isabell Matuschek, Nicola Balboni, S. J.Kumari A. Ubhayasekera, Marteinn Thor Snaebjornsson, Kamil Makowski, Kristina Aaltonen, Daniel Bexell, Dolors Serra, Roland Nilsson, Jonas Bergquist, Almut Schulze, Marie Arsenian-Henriksson

Research output: Contribution to journalArticlepeer-review

6 Citations (SciVal)

Abstract

Many metabolic pathways, including lipid metabolism, are rewired in tumors to support energy and biomass production and to allow adaptation to stressful environments. Neuroblastoma is the second deadliest solid tumor in children. Genetic aberrations, as the amplification of the MYCN-oncogene, correlate strongly with disease progression. Yet, there are only a few molecular targets successfully exploited in the clinic. Here we show that inhibition of fatty acid synthesis led to increased neural differentiation and reduced tumor burden in neuroblastoma xenograft experiments independently of MYCN-status. This was accompanied by reduced levels of the MYCN or c-MYC oncoproteins and activation of ERK signaling. Importantly, the expression levels of genes involved in de novo fatty acid synthesis showed prognostic value for neuroblastoma patients. Our findings demonstrate that inhibition of de novo fatty acid synthesis is a promising pharmacological intervention strategy for the treatment of neuroblastoma independently of MYCN-status.

Original languageEnglish
Article number102128
JournaliScience
Volume24
Issue number2
DOIs
Publication statusPublished - 2021

Bibliographical note

Funding Information:
We are indebted to Professor C. Einvik (Artic University of Norway, Troms?, Norway) for the BE(2)sh MYCN cell line, to Professor M. Schwab (German Cancer Research Center, Heidelberg, Germany) for the Tet-21/N cells, to Professor Rolf M?ller (Helmholtz Institute for Pharmaceutical Research Saarland, Saarland, Germany) for kindly providing Soraphen A, and to Dr. X. Ariza for participating in the synthesis of UB006. We are grateful to Dr. K. Hultenby and the KI TEM core facility for excellent analysis, Professor H. Hertz and K. Andersson (Royal Institute of Technology, Stockholm) for providing infrastructure for mouse experiments and for expert assistance with animal work, respectively. We acknowledge Dr. J. Milosevic (Massachusetts General Hospital, Boston, United States) for kindly providing the drawing of a child with neuroblastoma. We are thankful to Drs. C. L?kke (Arctic University of Norway, Troms?, Norway) and L. Herrero (University of Barcelona, Barcelona, Spain) for advice, to Professor S. Lain, Dr. N. Baryawno, Dr. M. Wilhelm, and members of the Wilhelm and Arsenian-Henriksson laboratories (all KI) for fruitful discussions, and to Dr. L. Herrero for critical reading of the manuscript. This work was supported by grants to MAH from the Swedish Cancer Society (19-0510), the Swedish Childhood Cancer Fund (PR-2018-0026), the Swedish Research Council (2018-02580), the King Gustaf V Jubilee Fund, and Karolinska Institutet Foundations and to MVRP by grants from the Anna-Brita and Bo Castegren's Memorial Fund and KI Foundations. MVRP was the recipient of a postdoctoral position from the Swedish Childhood Cancer Fund and MAH of a Senior Investigator Award from the Swedish Cancer Society. IM and NB received ERASMUS funding. DS and KM were founded by the CIBER Physiopathology of Obesity and Nutrition (CB06/03/001), the Government of Catalonia (2017SGR278), and the TV3 Marat? Foundation (201627-30). MTS was funded by the German Research Foundation (DFG, FOR2314). MVRP and MAH designed the study. MVRP performed cell and molecular biology assays and patient data analysis. MVRP and LSA performed western blots, functional metabolic assays, mouse studies, and tumor stainings. GO carried out functional metabolic experiments, and IM and NB performed western blots and qPCRs. DS and KM synthesized and provided UB006. KA and DB contributed the PDX cells and expertise. MVRP, MAH, MTS, and AS designed, performed, and analyzed tracing and metabolomics experiments. RN provided metabolic tracers and participated in the analysis of the results. MVRP, MAH, KU, and JB designed, performed, and analyzed lipid species quantification experiments. MVRP and MAH wrote the manuscript. All authors read and commented on the text. The authors declare no competing interests.

Funding Information:
We are indebted to Professor C. Einvik (Artic University of Norway, Tromsö, Norway) for the BE(2)sh MYCN cell line, to Professor M. Schwab (German Cancer Research Center, Heidelberg, Germany) for the Tet-21/N cells, to Professor Rolf Müller (Helmholtz Institute for Pharmaceutical Research Saarland, Saarland, Germany) for kindly providing Soraphen A, and to Dr. X. Ariza for participating in the synthesis of UB006. We are grateful to Dr. K. Hultenby and the KI TEM core facility for excellent analysis, Professor H. Hertz and K. Andersson (Royal Institute of Technology, Stockholm) for providing infrastructure for mouse experiments and for expert assistance with animal work, respectively. We acknowledge Dr. J. Milosevic (Massachusetts General Hospital, Boston, United States) for kindly providing the drawing of a child with neuroblastoma. We are thankful to Drs. C. Lökke (Arctic University of Norway, Tromsö, Norway) and L. Herrero (University of Barcelona, Barcelona, Spain) for advice, to Professor S. Lain, Dr. N. Baryawno, Dr. M. Wilhelm, and members of the Wilhelm and Arsenian-Henriksson laboratories (all KI) for fruitful discussions, and to Dr. L. Herrero for critical reading of the manuscript. This work was supported by grants to MAH from the Swedish Cancer Society ( 19-0510 ), the Swedish Childhood Cancer Fund ( PR-2018-0026 ), the Swedish Research Council (2018- 02580 ), the King Gustaf V Jubilee Fund , and Karolinska Institutet Foundations and to MVRP by grants from the Anna-Brita and Bo Castegren’s Memorial Fund and KI Foundations . MVRP was the recipient of a postdoctoral position from the Swedish Childhood Cancer Fund and MAH of a Senior Investigator Award from the Swedish Cancer Society . IM and NB received ERASMUS funding. DS and KM were founded by the CIBER Physiopathology of Obesity and Nutrition ( CB06/03/001 ), the Government of Catalonia ( 2017SGR278 ), and the TV3 Marató Foundation ( 201627-30 ). MTS was funded by the German Research Foundation (DFG, FOR2314 ).

Publisher Copyright:
© 2021 The Author(s)

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Subject classification (UKÄ)

  • Cancer and Oncology

Keywords

  • biological sciences
  • cancer
  • cell biology
  • molecular biology

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