MYCN is a member of the MYC family of proto-oncogenes. It encodes a transcription factor, MYCN, involved in the control of fundamental processes during embryonal development. The MYCN protein is situated downstream of several signaling pathways promoting cell growth, proliferation and metabolism of progenitor cells in different developing organs and tissues. Conversely, deregulated MYCN signaling supports the development of several different tumors, mainly with a childhood onset, including neuroblastoma, medulloblastoma, rhabdomyosarcoma and Wilms’ tumor, but it is also associated with some cancers occurring during adulthood such as prostate and lung cancer. In neuroblastoma, MYCN-amplification is the most consistent genetic aberration associated with poor prognosis and treatment failure. Targeting MYCN has been proposed as a therapeutic strategy for the treatment of these tumors and great efforts have allowed the development of direct and indirect MYCN inhibitors with potential clinical use.

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.

Exercise has a range of effects on metabolism. In animal models, repeated exertion reduces malignant tumour progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effect of exercise on tumour progression is unclear, as are the cellular actors involved. We show here that exercise-induced reduction in tumour growth is dependent on CD8+ T cells and that lactate, which is produced at high levels during exertion, increases proliferative capacity and cytotoxicity of CD8+ T cells. We found that at elevated levels lactate is used as a fuel during T cell activation. We further found that injection of lactate into animals can reduce malignant tumour growth in a dose-and CD8+ T cell-dependent manner. These data demonstrate that lactate can act to increase the anti-tumour activity of cytotoxic T cells, and in so doing, reduce cancer progression.