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

doi:10.1016/j.isci.2021.102128

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

iScience. 2021 Feb 1;24(2):102128. doi: 10.1016/j.isci.2021.102128. eCollection 2021 Feb 19.

Authors

María Victoria Ruiz-Pérez¹, Lourdes Sainero-Alcolado¹, Ganna Oliynyk¹, Isabell Matuschek¹, Nicola Balboni¹, S J Kumari A Ubhayasekera², Marteinn Thor Snaebjornsson³, Kamil Makowski⁴, Kristina Aaltonen⁵, Daniel Bexell⁵, Dolors Serra⁶, Roland Nilsson^{7

8

9}, Jonas Bergquist², Almut Schulze³, Marie Arsenian-Henriksson¹

Affiliations

¹ Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum B7, Karolinska Institutet, 171 65 Stockholm, Sweden.
² Analytical Chemistry, Department of Chemistry and Science for Life Laboratory, Uppsala University, 751 24 Uppsala, Sweden.
³ Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁴ Department of Inorganic and Organic Chemistry, Section of Organic Chemistry, Faculty of Chemistry, University of Barcelona, 08028 Barcelona, Spain.
⁵ Translational Cancer Research, Lund University, 22381 Lund, Sweden.
⁶ Department of Biochemistry and Physiology, School of Pharmacy, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain, and CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, 28029 Madrid, Spain.
⁷ Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.
⁸ Division of Cardiovascular Medicine, Karolinska University Hospital, 17176 Stockholm, Sweden.
⁹ Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.

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.

Keywords: biological sciences; cancer; cell biology; molecular biology.