Transcriptional Profiling Reveals a Common Metabolic Program in High-Risk Human Neuroblastoma and Mouse Neuroblastoma Sphere-Forming Cells

Abstract

Summary High-risk neuroblastoma remains one of the deadliest childhood cancers. Identification of metabolic pathways that drive or maintain high-risk neuroblastoma may open new avenues of therapeutic interventions. Here we report the isolation and propagation of neuroblastoma sphere-forming cells with self-renewal and differentiation potential from tumors of TH-MYCN mice, an animal model of high-risk neuroblastoma with MYCN amplification. Transcriptional profiling reveals that mouse neuroblastoma sphere-forming cells acquire a metabolic program characterized by transcriptional activation of the cholesterol and serine-glycine synthesis pathways, primarily as a result of increased expression of sterol regulatory element-binding factors and Atf4, respectively. This metabolic reprogramming is recapitulated in high-risk human neuroblastomas and is prognostic for poor clinical outcome. Genetic and pharmacological inhibition of the metabolic program markedly decreases the growth and tumorigenicity of both mouse neuroblastoma sphere-forming cells and human neuroblastoma cell lines. These findings suggest a therapeutic strategy for targeting the metabolic program of high-risk neuroblastoma.

Therapeutic Targeting of Non-oncogene Dependencies in High-risk Neuroblastoma

“…For example, the serine pathway genes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and serine hydroxymethyltransferase 2 (SHMT2), the one-carbon metabolism genes methylenetetrahydrofolate dehydrogenase (NADP þ -dependent) 2, methenyltetrahydrofolate cyclohydrolase (MTHFD2), MTHFD1 and dihydrofolate reductase (DHFR), and the nucleotide biosynthesis genes guanine monophosphate synthase (GMPS), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), PAICS, phosphoribosyl pyrophosphate amidotransferase (PPAT) and thymidylate synthetase (TYMS) were successfully captured in MYCN-amplified neuroblastoma ( Supplementary Figs. S3B, S6A, and S7A; Supplementary Table S4), consistent with direct MYC(N) target genes (45)(46)(47)(48) and a cooperative role in fueling tumor growth (49)(50)(51). Moreover, several of these metabolism genes have been reported to be overexpressed in many other cancers (such as MTHFD2, GMPS, SHMT2, TYMS, and PAICS; ref.…”

Increased Cholesterol Biosynthesis Is a Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome

“…Here, we identified a highly active metabolic program associated with cholesterol biosynthesis as an additional pathway central for CSCs, a finding established by proteomic profiling comparing paired samples of patient tumor tissue, derived PDXs, and mammospheres, known to be enriched for CSCs. In general, cholesterol plays an important role in the structure of membranes and the function of membrane-localized proteins, as well as in cell proliferation and cell survival (Goldstein and Brown, 1990;Liu et al, 2016). In breast cancer, total cholesterol is a poor prognostic factor (Boyd and McGuire, 1990;Ferraroni et al, 1993;Kitahara et al, 2011), and statin use has been associated with increased recurrence-free survival (Ahern et al, 2011;Nielsen et al, 2012;Borgquist et al, 2017).…”

Menin regulates the serine biosynthetic pathway in Ewing sarcoma

“…Serine and glycine serve as major sources of metabolic intermediates that are required for the synthesis of nucleotides, phospholipids, and ATP, as well for the maintenance of redox homeostasis and regulation of DNA and histone methylation [15,18,19]. Activation of the SSP in cancer has been linked to genomic amplification of the PHGDH locus [16,20], as well as to transcriptional and epigenetic [17,[21][22][23][24][25] mechanisms. PHGDH is not amplified in Ewing sarcoma [26][27][28], implicating alternative mechanisms in maintaining oncogenic activation of the SSP.…”