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Fultang, Livingstone; Gamble, Laura D; Gneo, Luciana; Berry, Andrea M; Egan, Sharon A; De Bie, Fenna; Yogev, Orli; Eden, Georgina L; Booth, Sarah; Brownhill, Samantha; Vardon, Ashley; McConville, Carmel M; Cheng, Paul N; Norris, Murray D; Etchevers, Heather C; Murray, Jayne; Ziegler, David S; Chesler, Louis; Schmidt, Ronny; Burchill, Susan A; Haber, Michelle; De Santo, Carmela; Mussai, Francis
Cancer research, 02/2019, Volume: 79, Issue: 3Journal Article
Neuroblastoma is the most common childhood solid tumor, yet the prognosis for high-risk disease remains poor. We demonstrate here that arginase 2 (ARG2) drives neuroblastoma cell proliferation via regulation of arginine metabolism. Targeting arginine metabolism, either by blocking cationic amino acid transporter 1 (CAT-1)-dependent arginine uptake or therapeutic depletion of arginine by pegylated recombinant arginase BCT-100, significantly delayed tumor development and prolonged murine survival. Tumor cells polarized infiltrating monocytes to an M1-macrophage phenotype, which released IL1β and TNFα in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. IL1β and TNFα established a feedback loop to upregulate ARG2 expression via p38 and extracellular regulated kinases 1/2 (ERK1/2) signaling in neuroblastoma and neural crest-derived cells. Proteomic analysis revealed that enrichment of IL1β and TNFα in stage IV human tumor microenvironments was associated with a worse prognosis. These data thus describe an immune-metabolic regulatory loop between tumor cells and infiltrating myeloid cells regulating ARG2, which can be clinically exploited. SIGNIFICANCE: These findings illustrate that cross-talk between myeloid cells and tumor cells creates a metabolic regulatory loop that promotes neuroblastoma progression.
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