PMCID string | Title string | Sentences string |
|---|---|---|
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Data are mean ± s.e.m., |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | n = 6. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | f, Schematic of tumour metabolite sources in neuroblastoma. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | The amino acids proline and arginine are primarily taken up from circulation. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Tracing identifies the polyamine precursor ornithine to be primarily derived from circulation and not from intratumoral biosynthesis. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Arginine is the primary circulatory substrate for ornithine production. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | In the intestine, ornithine is produced from arginine and proline through OAT activity. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Panels a, c, e and f created in BioRender. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Morscher, R. (2025) https://BioRender.com/ntr5665 (a); https://BioRender.com/x0bpqyh (c); https://BioRender.com/50lb1xh (e); https://BioRender.com/3h88n1g (f).Source data a, Primary neuroblastoma tumour tissue was analysed using liquid chromatography–mass spectrometry-based metabolomics. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | b, Differential abundance of 303 metabolites. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Proline was the most significantly increased metabolite in MYCN-amplified primary human neuroblastoma relative to non-amplified tumours. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Dotted line marks the significance threshold, with P values corrected for a false discovery rate (FDR) of 0.05 (q < 0.05; n = 10). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | c, In vivo stable isotope tracing identifies the circulating precursors of intratumoral metabolites. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Labelling is normalized to the serum for each infused [U-C] metabolite in Th-MYCN mice fed a chow diet. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Data are mean ± s.e.m. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Proline serum: n = 6; proline tumour: n = 4; glutamine serum: n = 9; glutamine tumour: n = 9; arginine serum: n = 8; arginine tumour: n = 8; ornithine serum: n = 7; ornithine tumour: n = 6. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | d, Direct circulating nutrient contributions to tumour tissue metabolite pools of proline, arginine and ornithine in Th-MYCN mice. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | The colour indicates the respective circulating nutrient source. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Contributions derived from [U-C]-labelled tracer infusions, derived from data shown in c. Data are mean ± s.e.m. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | e, Oral gavage of C-labelled nutrients shows the dietary contribution to circulating ornithine. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | The gavage feed introduces one-third of the daily intake of the respective amino acid in its [U-C] form, which is used to quantify its contribution to polyamine-related downstream metabolites over time. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Feeds in the Th-MYCN model are adapted to mouse weight. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Data are mean ± s.e.m., |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | n = 6. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | f, Schematic of tumour metabolite sources in neuroblastoma. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | The amino acids proline and arginine are primarily taken up from circulation. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Tracing identifies the polyamine precursor ornithine to be primarily derived from circulation and not from intratumoral biosynthesis. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Arginine is the primary circulatory substrate for ornithine production. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | In the intestine, ornithine is produced from arginine and proline through OAT activity. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Panels a, c, e and f created in BioRender. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Morscher, R. (2025) https://BioRender.com/ntr5665 (a); https://BioRender.com/x0bpqyh (c); https://BioRender.com/50lb1xh (e); https://BioRender.com/3h88n1g (f). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Source data As a complementary approach to identify metabolic targets, we first investigated the in vivo circulatory sources of proline and ornithine using infusion-based stable isotope tracing in the Th-MYCN model. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Tumour proline was derived from circulating proline and glutamine, reflecting proline acquisition from a combination of circulatory uptake and de novo biosynthesis (Fig. 1c). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Unlike in previous studies in infants, this proline was not converted to ornithine in substantial quantities in the neuroblastoma tumours. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Examination of gene-expression data from primary tumours revealed that OAT expression is low in MYCN-driven neuroblastoma (Extended Data Fig. 2b), consistent with the need for an alternative ornithine source rather than intratumour synthesis from glutamine or proline. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Isotope tracing confirmed the source to be circulating arginine and ornithine itself. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Most circulating ornithine was derived from arginine (Fig. 1c and Extended Data Fig. 3) and to a lesser extent from dietary, but not circulating, proline (Fig. 1e). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | A large fraction of oral arginine was also converted to circulating proline, highlighting carbons being diverted from ornithine to proline synthesis by intestinal OAT activity (Extended Data Fig. 3b). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Tumour ornithine was most strongly labelled from circulating ornithine, although it was also strongly labelled from circulating arginine. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Quantitative modelling analysis of tumour ornithine sources revealed that circulating arginine feeds tumour ornithine mainly indirectly, after being converted to ornithine elsewhere in the body, and subsequent uptake of the resulting circulating ornithine by the tumour (Fig. 1d and Extended Data Fig. 3c,d). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | The ultimate upstream source of most neuroblastoma ornithine under a standard diet is therefore arginine, highlighting arginine restriction as a potential complement to proline restriction and DFMO treatment for neuroblastoma therapy. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | To test this, we introduced a proline- and arginine-free (ProArg-free) diet (Supplementary Table 2) in the Th-MYCN mouse model and assessed its effect on metabolic networks by in vivo tracing. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | The ProArg-free diet reduced circulating fluxes of proline, arginine, glutamine and ornithine (Extended Data Fig. 3e,f). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Nonetheless, infusion-based tracing showed largely unchanged labelling of intratumoral polyamine-related metabolites, with uptake from circulation remaining the predominant source of ornithine (Extended Data Fig. 3g). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | This indicates that even under a diet depleted of its ornithine substrates, intratumoral OAT directionality is maintained with only minor local ornithine production in neuroblastoma (Extended Data Fig. 3f,h). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | By contrast, pre-circulatory intestinal conversion of dietary proline to ornithine via OAT doubled under the ProArg-free diet to support systemic ornithine levels (Extended Data Fig. 3i,j). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Ornithine is then converted to polyamines locally in the tumours, as evidenced by the contribution to putrescine labelling, with increased labelling from ornithine upon a ProArg-free diet (Extended Data Fig. 3k) and lower contribution from circulating putrescine (Extended Data Fig. 3l). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | We therefore evaluated the anti-tumour effect of dietary substrate depletion of the two major amino acid precursors of ornithine (Fig. 1f) in combination with DFMO treatment. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Using the Th-MYCN model, we next examined the effect of combined dietary amino acid depletion (proline and/or arginine) with or without pharmacological ODC inhibition by DFMO (Fig. 2a). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Mice fed the ProArg-free diet alone showed reduced neuroblastoma growth compared with control diet (CD), with no effect on tumour-free survival (Fig. 2b,c). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | As in previous studies, inhibition of polyamine biosynthesis by DFMO monotherapy extended survival. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | In mice with prolonged survival, lethal tumour progression was observed after treatment cessation. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Fig. 2A ProArg-free diet enhances tumour growth suppression by DFMO in MYCN-driven neuroblastoma.a, Schematic of two-factor intervention, including the ProArg-free diet (from day 21) and DFMO treatment via the drinking water (1%, from day 0 to nursing mothers and directly to pups from day 28) in the Th-MYCN genetically modified mouse model. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | b, Kaplan–Meier curve of tumour-free survival with combined CD or ProArg-free diet plus DFMO. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | P value from log-rank test compared to CD. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | c, Tumour growth, defined as tumour mass at death normalized by day of life. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Two-tailed t-test compared to CD. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Data are mean ± s.e.m. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | CD: n = 13; CD + DFMO: n = 14; ProArg-free: n = 13; ProArg-free + DFMO: n = 14. * |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Panel a created in BioRender. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Morscher, R. (2025) https://BioRender.com/n9dgse0.Source data a, Schematic of two-factor intervention, including the ProArg-free diet (from day 21) and DFMO treatment via the drinking water (1%, from day 0 to nursing mothers and directly to pups from day 28) in the Th-MYCN genetically modified mouse model. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | b, Kaplan–Meier curve of tumour-free survival with combined CD or ProArg-free diet plus DFMO. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | P value from log-rank test compared to CD. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | c, Tumour growth, defined as tumour mass at death normalized by day of life. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Two-tailed t-test compared to CD. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Data are mean ± s.e.m. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | CD: n = 13; CD + DFMO: n = 14; ProArg-free: n = 13; ProArg-free + DFMO: n = 14. * |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Panel a created in BioRender. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Morscher, R. (2025) https://BioRender.com/n9dgse0. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Source data Notably, combining dietary proline and arginine removal with DFMO induced a marked survival benefit (Fig. 2b), decreased tumour growth (Fig. 2c) and increased time to detectable tumour (Extended Data Fig. 4a,b). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | One-third of mice in the ProArg-free diet plus DFMO regimen had extended survival, with approximately 20% remaining tumour-free, as confirmed via necropsy. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Although the ProArg-free diet caused a reduction in mouse weight, this did not affect survival and was not worsened by adding DFMO (Extended Data Fig. 4c,d). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | The therapeutic effect of combining DFMO with dietary depletion of either proline or arginine alone was inferior to DFMO plus ProArg-free diet (Extended Data Fig. 4e–g). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Even when delaying treatment initiation until pre-terminal tumour progression, we observed a significant reduction in tumour mass in the ProArg-free diet plus DFMO regimen, suggesting relevance for treatment of established tumours (Extended Data Fig. 4h,i). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Despite the unfavourable metabolic environment, a higher immune cell infiltration and stromal component was observed in the ProArg-free, DFMO-treated tumours (Supplementary Fig. 1). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | In summary, the ODC inhibitor DFMO, which was recently approved by the US Food and Drug Administration for neuroblastoma treatment, combined with a diet free of the non-essential amino acids arginine and proline, significantly augments anti-tumour activity with around 20% of treated mice remaining tumour-free 100 days beyond the end of therapy. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | To reveal the metabolic reprogramming underlying this anti-tumour activity, we performed serum metabolomics (Fig. 3 and Extended Data Fig. 5a). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Across the entire metabolome, the metabolite showing the most significant decrease in serum in response to the ProArg-free diet was ornithine, the crucial polyamine precursor that we sought to deplete. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | The next two most significantly decreased metabolites were proline and arginine themselves (Fig. 3b,c and Extended Data Fig. 5b,c). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Other notable serum metabolite changes included an increase in glutamine and decreases in citrulline and the collagen breakdown product hydroxyproline (Fig. 3b,c and Extended Data Fig. 5c). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Arginine, proline and ornithine were also significantly decreased in tumours following different treatment durations, but to a lesser extent than in serum (Fig. 3d and Extended Data Fig. 5d,e). |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | The depletion of intratumoral ornithine manifested despite the increase in tumour glutamine, which gives rise to ornithine in other cancers via OAT.Fig. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | 3Dietary intervention causes substrate depletion to enhance polyamine biosynthesis inhibition by DFMO.a, Schematic of arginine, proline and glutamine metabolism and its direct link to polyamines via ornithine. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | GSAL, glutamate-γ-semialdehyde; P5C, pyrroline-5-carboxylate. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | b, Differential serum metabolite levels comparing ProArg-free diet with CD. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Blue dots highlight metabolites that are significantly depleted (FDR < 0.05) and the rose dot indicates a metabolite that was upregulated compared with CD. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | CD: n = 8; ProArg-free: n = 7. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | c, Serum arginine, proline, glutamine and ornithine across groups. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Statistical comparisons to CD. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Data are mean ± s.e.m. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | CD: n = 8; CD + DMFO: n = 10; ProArg-free: n = 7; ProArg-free + DFMO: n = 7. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | d, Tumour arginine, proline, glutamine and ornithine levels reveal dysregulation of arginine and proline metabolism with combined ProArg-free diet plus DFMO treatment. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Average age at end point is eight weeks. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Statistical comparisons to CD. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Data are mean ± s.e.m. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | CD: n = 5; CD + DMFO: n = 5; ProArg-free: n = 8; ProArg-free + DFMO: n = 4. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | e, A ProArg-free diet enhances polyamine depletion in tumour tissue induced by DFMO in prolonged treatment. |
PMC12527938 | Reprogramming neuroblastoma by diet-enhanced polyamine depletion | Average age at end point is 12 weeks. |
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