Abstract 1680: Therapeutically targeting genes and pathways activated by high-fat diet in high-risk neuroblastoma

Abstract MYCN-amplified neuroblastoma (NB) is one of the most aggressive and treatment refractory cancers in children. NB has a prenatal origin, and therefore environmental factors in utero may play a critical role in driving NB tumorigenesis. A recent epidemiological study showed that children born to mothers who gained weight more than 30 kg during pregnancy had a 2-fold higher risk of developing NB. Using the Th-MYCN NB transgenic mouse model, we found that high-fat diet (HFD)-induced maternal obesity resulted in accelerated NB tumorigenesis in the Th-MYCN homozygous offspring. Transcriptomic patterns in tumour tissues from Th-MYCN homozygous offspring of HFD-fed mothers showed upregulation of fatty acid (FA) metabolism and mitochondrial oxidative phosphorylation (OXPHOS) pathways. We then used human NB cell lines exposed to excess FA to study mechanisms and therapeutics. In vitro studies showed that excess FA increased growth, proliferation, and colony formation in human NB cell lines, which was reversed by Fatostatin, a FA metabolism inhibitor, with an effect which was partially MYCN-dependent. Fatostatin showed significant synergy in combination with doxorubicin and vincristine in reversing FA-accelerated growth, proliferation, and colony formation in human NB cell lines, with a wide therapeutic window. ATP5G1 and ATP5G2 (genes encoding human mitochondrial ATP synthase membrane c-subunit) were identified as candidate genes in the HFD-activated OXPHOS pathways. siRNA knockdown of both genes significantly reversed FA-accelerated growth and proliferation in human NB cell lines. Chromatin immunoprecipitation (ChIP)-PCR showed that ATP5G1 and ATP5G2 are transcriptional targets of MYCN, and their transcription is significantly increased in the presence of FA. Further, the overall ATP production was significantly increased in the presence of FA in human NB cell lines, but not in human normal fibroblasts. siRNA knockdown of ATP5G1 and ATP5G2 significantly decreased this effect. Together, our data strongly support a role for OXPHOS and FA metabolism pathways in HFD-accelerated NB tumorigenesis and highlight a key role of the mitochondrial ATP synthase membrane c-subunit genes, ATP5G1 and ATP5G2 in HFD-accelerated NB tumorigenesis. Citation Format: Md Jahidul Hasan, Ritu Mittra, Marie Joseph, Mukesh Raipuria, 1 Nisitha Jayatilleke, Daniel R Carter, Margaret J Morris, Belamy B Cheung, Glenn M Marshall. Therapeutically targeting genes and pathways activated by high-fat diet in high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1680.